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Cited by 245Vitamin D Research StudiesMetabolomics and Mass Spectrometry StudiesParathyroid Disorders and Treatments

The serum vitamin D metabolome: what we know and what is still to discover

Open access
Tuckey, Robert C., Cheng, Chloe Y.S., Slominski, Andrzej T.·2019·The Journal of Steroid Biochemistry and Molecular Biology
DOI 10.1016/j.jsbmb.2018.09.003PMC PMC6342654
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Abstract

Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1α,25-dihydroxyvitamin D (1α,25(OH)2D), formed from vitamin D via 25hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1α,25(OH)2D. Inactivation of both 25(OH)D and 1α,25(OH)2D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)2D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1α,25(OH)2D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)2D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.

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Crossref · 10.1016/j.jsbmb.2018.09.003

Cites

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Claims the paper makes

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  • Findingown data

    Human CYP27B1 is highly specific for 1α-hydroxylation across a range of endogenously produced vitamin D metabolites.

    “This enabled a detailed study of its substrate specificity to be carried out in a reconstituted membrane environment which revealed that CYP27B1 was highly specific for catalyzing 1α-hydroxylation on a range of endogenously-produced vitamin D metabolites.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    The most efficient step in 1α,25(OH)2D3 C24-oxidation is cleavage of 24-oxo-1α,23S,25(OH)3D3 between C23 and C24, producing 1α(OH)-23-oxo-tetranorvitamin D3 rather than the previously reported 1α,23(OH)2-tetranorvitamin D3.

    “The most efficient step in the metabolism of 1α,25(OH)2D3 by the C24oxidation pathway was cleavage of the side chain of 24-oxo-1α,23S,25(OH)3D3 between C23 and C24 where the initial product was identified as 1α(OH)-23-oxo-tetranorvitamin D3 and not the 1α,23(OH)2tetranorvitamin D3 previously reported in the literature (see Fig. 3) [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Jones G, Prosser DE, Kaufmann M, 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D, Archives of biochemistry and biophysics, 523 (2012) 9– 18. 22100522

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  • Findingnone given

    The mean 24R,25(OH)2D3 concentration differs substantially among the four studies listed in Table 2.

    “Its mean concentration varies considerably between the four studies listed in Table 2.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Chromatographic separation by LC before MS/MS is essential for measuring specific vitamin D forms in serum.

    “Therefore, chromatographic separation of the various forms of vitamin D present in the serum by LC prior to MS/MS is crucial to the measurement of specific forms of vitamin D.”
    Quote in the paperSubstantial claim
  • Premisenone given

    20S(OH)D3 is the best characterized product of the CYP11A1 alternative activation pathway.

    “20S(OH)D3 is the best characterized product of this pathway.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 110
  • Classified as probably not a substantial claim. 25

  • May combine two claims.

    Findingown data

    The ratio of initial C24 to C23 hydroxylation products by human CYP24A1 is 4:1, indicating that the C24-oxidation pathway predominates in humans.

    “We observed that the ratio of initial hydroxylation products at C24 to C23 was 4:1, in agreement with the results of Sakaki et al [112], indicating that the C24-oxidation pathway predominates in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Sakaki T, Sawada N, Komai K, Shiozawa S, Yamada S, Yamamoto K, Ohyama Y, Inouye K, Dual metabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24, European journal of biochemistry, 267 (2000) 6158– 6165. 11012668

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  • May combine two claims.

    Findingcitation

    Recombinant human CYP11A1 and CYP11A1 in human placental mitochondria can catalyze these vitamin D hydroxylations.

    “We also confirmed that the recombinant human enzyme and CYP11A1 in mitochondria from the human placenta could catalyze these hydroxylations [122].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Slominski AT, Kim TK, Shehabi HZ, Semak I, Tang EK, Nguyen MN, Benson HA, Korik E, Janjetovic Z, Chen J, Yates CR, Postlethwaite A, Li W, Tuckey RC, In vivo evidence for a novel pathway of vitamin D(3) metabolism initiated by P450scc and modified by CYP27B1, FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 26 (2012) 3901– 3915. 22683847 PMC3425822 source

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  • May combine two claims.

    Findingnone given

    For human CYP27B1, catalytic efficiencies for 1α-hydroxylation of 25(OH)D3, 25(OH)D2 and 24R,25(OH)2D3 were fairly similar but lower for 24-oxo-25(OH)D3 and 24-oxo-23,25(OH)2D3.

    “Catalytic efficiencies for 1α-hydroxylation of 25(OH)D3, 25(OH)D2 and 24R,25(OH)2D3 were fairly similar but lower for 24-oxo-25(OH)D3 and 24-oxo-23,25(OH)2D3, later intermediates of the C24-oxidation pathway of vitamin D3 inactivation by CYP24A1 (see Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Human CYP27B1 acts on CYP11A1-derived hydroxyvitamin D products, with catalytic efficiencies from undetectable for 17α-OH substrates to three times higher than 25(OH)D3 1α-hydroxylation for 20S,24R(OH)2D3 and 20S,25(OH)2D3.

    “Human CYP27B1 also acted on hydroxyvitamin D products of CYP11A1 action on vitamin D (see Fig. 4) with catalytic efficiencies ranging from undetectable for substrates with a 17α-OH group such as 17α,20S(OH)2D3, to efficiencies three times higher than that for 1α-hydroxylation of 25(OH)D3 for 20S,24R(OH)2D3 and 20S,25(OH)2D3 [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Tang EK, Chen J, Janjetovic Z, Tieu EW, Slominski AT, Li W, Tuckey RC, Hydroxylation of CYP11A1-derived products of vitamin D3 metabolism by human and mouse CYP27B1, Drug metabolism and disposition: the biological fate of chemicals, 41 (2013) 1112– 1124. 23454830 PMC3629803 source

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    Findingown data

    In the authors' reconstituted system, human CYP24A1 had a 3-fold higher catalytic efficiency for 25(OH)D3 than for 1α,25(OH)2D3, contrasting with a reported 1.7-fold higher efficiency for 1α,25(OH)2D3 in bacterial membranes.

    “These workers reported that the catalytic efficiency for 24hydroxylation of 1α,25(OH)2D3 by CYP24A1 in bacterial membranes was 1.7-fold higher than for 25(OH)D3, however our own studies with partially purified enzyme in a reconstituted system resembling the inner mitochondrial membrane (described next), showed that the catalytic efficiency was 3-fold higher for 25(OH)D3 than for 1α,25(OH)2D3 [113]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Tieu EW, Tang EK, Tuckey RC, Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway, The FEBS journal, 281 (2014) 3280– 3296. 24893882

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    Findingcitation

    C23 and C17 are also major hydroxylation sites for CYP11A1 acting on vitamin D3, and no side-chain cleavage occurs.

    “We extended these observations showing that C23 and C17 were also major sites of hydroxylation, but that no cleavage of the side chain occurred [119–121], leading to the pathway described in Fig. 4.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [119] Slominski A, Semak I, Zjawiony J, Wortsman J, Li W, Szczesniewski A, Tuckey RC, The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism, The FEBS journal, 272 (2005) 4080– 4090. 16098191 PMC2234577 source

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    • cites [120] Tuckey RC, Li W, Zjawiony JK, Zmijewski MA, Nguyen MN, Sweatman T, Miller D, Slominski A, Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc, The FEBS journal, 275 (2008) 2585– 2596. 18410379 PMC2562691 source

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    • cites [121] Tuckey RC, Li W, Shehabi HZ, Janjetovic Z, Nguyen MN, Kim TK, Chen J, Howell DE, Benson HA, Sweatman T, Baldisseri DM, Slominski A, Production of 22-hydroxy metabolites of vitamin D3 by cytochrome P450scc (CYP11A1) and analysis of their biological activities on skin cells, Drug metabolism and disposition: the biological fate of chemicals, 39 (2011) 1577– 1588. 21677063 PMC3164270 source

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    Findingcitation

    The reported mean vitamin D3 concentration of 7.5 nM is comparable to 6.0 nM found in another study by the authors.

    “The vitamin D3 concentration compares well to that of 6.0 nM reported in a separate study by us [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EK, Tuckey RC, Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland, Sci Rep, 5 (2015) 14875. 26445902 PMC4597207

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    Findingcitation

    In semi-quantitative analysis of 13 adults, mean serum 20S(OH)D3 was 2.9 nM and 22(OH)D3 was 6.0 nM.

    “the mean serum concentrations of 20S(OH)D3 and 22(OH)D3 (from 13 adults) were 2.9 nM and 6.0 nM, respectively [152]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EK, Tuckey RC, Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland, Sci Rep, 5 (2015) 14875. 26445902 PMC4597207

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    Findingcitation

    20(OH)L3, 22-(OH)L3, 20,22-(OH)2L3 and pL were measured in serum, with 20-(OH)L3 highest at 25.2 nM, more than half the mean 25(OH)D3.

    “20(OH)L3, 22-(OH)L3, 20,22-(OH)2L3 and pL were also measured in serum with the 20-(OH)L3 concentration being highest at 25.2 nM, more than half the mean 25(OH)D3 concentrations listed in Table 2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Slominski AT, Kim TK, Hobrath JV, Janjetovic Z, Oak ASW, Postlethwaite A, Lin Z, Li W, Takeda Y, Jetten AM, Tuckey RC, Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols, Sci Rep, 7 (2017) 11434. 28900196 PMC5595834 source

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    Findingcitation

    Mean serum L3 concentration was 51 nM in 13 samples, 10 times higher than vitamin D3 (5.0 nM) and similar to serum 7DHC.

    “The mean concentration of L3 (51 nM) in 13 samples analyzed was 10 times higher than that of vitamin D3 (5.0 nM) and similar to the serum 7DHC concentration [225].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Slominski AT, Kim TK, Hobrath JV, Janjetovic Z, Oak ASW, Postlethwaite A, Lin Z, Li W, Takeda Y, Jetten AM, Tuckey RC, Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols, Sci Rep, 7 (2017) 11434. 28900196 PMC5595834 source

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    Findingown data

    Preliminary unpublished incubations of tachysterol3 with pig adrenal glands and liver extracts generated mono- and dihydroxytachysterols by LC/MS, but lack of standards prevented full identification.

    “In preliminary studies in our laboratories (unpublished), incubations of tachysterol3 with pig adrenal glands and liver extracts led to the generation of species corresponding to mono- and dihydroxytachysterols by LC/MS, however the lack of chemical standards has, as yet, prevented their full identification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    1α,25(OH)2D is the major hormonally active vitamin D form and is essential for calcium and phosphorus homeostasis and skeletomuscular function.

    “It is well established that 1α,25(OH)2D is the major hormonally active form of vitamin D which plays a fundamental role in body calcium and phosphorous homeostasis, ensuring proper functioning of the skeletomuscular system [1, 6, 23–27].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [1] Holick MF, Vitamin D deficiency N Engl J Med, 357 (2007) 266– 281. 17634462 source

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    • cites [6] Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G, Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects, Physiol Rev, 96 (2016) 365– 408. 26681795 PMC4839493

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    • cites [23] DeLuca HF, Overview of general physiologic features and functions of vitamin D, Am J Clin Nutr, 80 (2004) 1689S– 1696S. 15585789

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    • cites [24] Holick MF, Vitamin D and bone health, J Nutr, 126 (1996) 1159S– 1164S. 8642450

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    • cites [25] Bikle DD, Vitamin D: an ancient hormone, Exp Dermatol, 20 (2011) 7– 13. 21197695

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    • cites [26] Pike JW, Christakos S, Biology and Mechanisms of Action of the Vitamin D Hormone, Endocrinol Metab Clin North Am, 46 (2017) 815– 843. 29080638 PMC5762112

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    • cites [27] van Driel M, van Leeuwen J, Vitamin D endocrinology of bone mineralization, Mol Cell Endocrinol, 453 (2017) 46– 51. 28606868

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    Premisecitation

    1α,25(OH)2D has pleiotropic effects on cell proliferation, differentiation, apoptosis, senescence, migration, and protective and reparative mechanisms.

    “However, over several decades evidence has accumulated for pleiotropic activities of 1α,25(OH)2D on different cell functions such as proliferation, differentiation, apoptosis, senescence, migration, and protective and reparative mechanisms.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [6] Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G, Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects, Physiol Rev, 96 (2016) 365– 408. 26681795 PMC4839493

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    • cites [28] Norman AW, Minireview: vitamin D receptor: new assignments for an already busy receptor, Endocrinology, 147 (2006) 5542– 5548. 16946007

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    • cites [29] Plum LA, DeLuca HF, Vitamin D, disease and therapeutic opportunities, Nat Rev Drug Discov, 9 (2010) 941– 955. 21119732

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    • cites [30] Mason RS, Reichrath J, Sunlight vitamin D and skin cancer, Anti-cancer agents in medicinal chemistry, 13 (2013) 83– 97. 23094924

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    • cites [31] Bikle DD, Elalieh H, Welsh J, Oh D, Cleaver J, Teichert A, Protective role of vitamin D signaling in skin cancer formation, J Steroid Biochem Mol Biol, 136 (2013) 271– 279. 23059470 PMC3596439

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    • cites [32] Fleet JC, DeSmet M, Johnson R, Li Y, Vitamin D and cancer: a review of molecular mechanisms, Biochem J, 441 (2012) 61– 76. 22168439 PMC4572477

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    • cites [33] Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ, The role of vitamin D in reducing cancer risk and progression, Nat Rev Cancer, 14 (2014) 342– 357. 24705652

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    • cites [34] Neme A, Seuter S, Carlberg C, Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor, Biochim Biophys Acta, 1860 (2017) 952961. 28712921

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  • May combine two claims.

    Premisecitation

    1α,25(OH)2D3 has anti-inflammatory and immunomodulatory properties, mainly downregulating adaptive and upregulating innate immunity, with preventive and therapeutic effects in autoimmune and inflammatory disorders.

    “Specifically, 1α,25(OH)2D3 shows anti-inflammatory and immunomodulatory properties (predominantly downregulation of adaptive and upregulation of innate immunity) having both preventive and therapeutic effects in autoimmune and inflammatory disorders [35–37].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Hewison M, Antibacterial effects of vitamin D, Nat Rev Endocrinol, 7 (2011) 337– 345. 21263449

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    • cites [36] Hewison M, An update on vitamin D and human immunity, Clin Endocrinol (Oxf), 76 (2012) 315– 325. 21995874

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    • cites [37] Vanherwegen AS, Gysemans C, Mathieu C, Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity, Endocrinol Metab Clin North Am, 46 (2017) 1061– 1094. 29080635

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    Premisecitation

    1α,25(OH)2D3 inhibits malignant transformation and tumor progression and has anti-cancer effects on gastrointestinal, genitourinary, breast, prostate, lung, and melanoma tumors.

    “It also inhibits malignant transformation, tumor progression and has anti-cancer properties on a variety of tumors including those of gastrointestinal, genitourinary, breast, prostate and lung origins [32, 33, 46, 51], as well as melanoma [52, 53].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [32] Fleet JC, DeSmet M, Johnson R, Li Y, Vitamin D and cancer: a review of molecular mechanisms, Biochem J, 441 (2012) 61– 76. 22168439 PMC4572477

      Not checked in the free run.

    • cites [33] Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ, The role of vitamin D in reducing cancer risk and progression, Nat Rev Cancer, 14 (2014) 342– 357. 24705652

      Not checked in the free run.

    • cites [46] Welsh J, Function of the vitamin D endocrine system in mammary gland and breast cancer, Mol Cell Endocrinol, 453 (2017) 88– 95. 28579119 PMC5538720

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    • cites [51] Masuda S, Jones G, Promise of vitamin D analogues in the treatment of hyperproliferative conditions, Mol Cancer Ther, 5 (2006) 797– 808. 16648549

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    • cites [52] Slominski AT, Brozyna AA, Skobowiat C, Zmijewski MA, Kim TK, Janjetovic Z, Oak AS, Jozwicki W, Jetten AM, Mason RS, Elmets C, Li W, Hoffman RM, Tuckey RC, On the role of classical and novel forms of vitamin D in melanoma progression and management, The Journal of steroid biochemistry and molecular biology, 177 (2018) 159– 170. 28676457 PMC5748362

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    • cites [53] Slominski AT, Brozyna AA, Zmijewski MA, Jozwicki W, Jetten AM, Mason RS, Tuckey RC, Elmets CA, Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management, Lab Invest, 97 (2017) 706– 724. 28218743 PMC5446295 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    1α,25(OH)2D3 is important in reproduction, pregnancy, placental function, and fetal and child development.

    “It plays an important role in reproduction, pregnancy, placental functions and fetal and child development [3843].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3843]

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    Premisereasoning

    Enzymatically synthesized secosteroids have been used as standards to identify vitamin D metabolites in serum and tissues and to confirm that the pathways operate in vivo.

    “These enzymatically-synthesized secosteroids have been used as standards to identify the metabolites in serum and tissues, and to confirm that the pathways operate in vivo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    20S(OH)D3 is highly potent in inhibiting proliferation and promoting differentiation of epidermal cells and in regulating immune cells and fibroblasts.

    “It displays high potency for the inhibition of proliferation and the promotion of differentiation in epidermal cells, and for the regulation of immune cells and fibroblasts (reviewed in [65–67]).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [65] Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, Tuckey RC, Novel activities of CYP11A1 and their potential physiological significance, The Journal of steroid biochemistry and molecular biology, 151 (2015) 25– 37. 25448732 PMC4757911 source

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    • cites [66] Slominski AT, Manna PR, Tuckey RC, On the role of skin in the regulation of local and systemic steroidogenic activities, Steroids, 103 (2015) 72– 88. 25988614 PMC4631694

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    • cites [67] Slominski AT, Kim TK, Li W, Yi AK, Postlethwaite A, Tuckey RC, The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions, The Journal of steroid biochemistry and molecular biology, 144PA (2014) 28– 39. PMC4002668 24176765 source

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    Premisecitation

    The effects of 24R,25(OH)2D3 are mediated by binding to FAM57B2 as an allosteric modulator, stimulating lactosylceramide synthesis and affecting cartilage maturation.

    “Very recently it was reported that the effects of 24R,25(OH)2D3 are mediated by its binding to the enzyme FAM57B2 on which it acts as an allosteric modulator, stimulating lactosylceramide synthesis which in turn affects cartilage maturation [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Martineau C, Naja RP, Husseini A, Hamade B, Kaufmann M, Akhouayri O, Arabian A, Jones G, St-Arnaud R, Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2, The Journal of clinical investigation, 128 (2018) 3546– 3557. 30010626 PMC6063485

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  • May combine two claims.

    Premisereasoning

    Studies using expressed and purified recombinant CYP enzymes have confirmed some established pathways and characterized new pathways of vitamin D metabolism.

    “Studies with the expressed and purified recombinant enzymes have enabled some of the already established pathways to be confirmed and new pathways to be characterized, as described below.”
    Quote in the paperSubstantial claim

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    Premisecitation

    24R,25(OH)2D3 can stimulate growth plate development and bone fracture repair and protect against osteoarthritis, but these effects do not appear to be mediated by VDR binding.

    “This metabolite can stimulate growth plate development and bonefracture repair, and protect against osteoarthritis, but these effects do not appear to be mediated by binding to the VDR [18, 19, 60–63].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [18] Boyan BD, Sylvia VL, McKinney N, Schwartz Z, Membrane actions of vitamin D metabolites 1alpha,25(OH)2D3 and 24R,25(OH)2D3 are retained in growth plate cartilage cells from vitamin D receptor knockout mice, Journal of cellular biochemistry, 90 (2003) 1207– 1223. 14635194

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    • cites [19] St-Arnaud R, Naja RP, Vitamin D metabolism, cartilage and bone fracture repair, Molecular and cellular endocrinology, 347 (2011) 48– 54. 21664253

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    • cites [60] St-Arnaud R, CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24, The Journal of steroid biochemistry and molecular biology, 121 (2010) 254– 256. 20144713

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    • cites [61] Boyan BD, Hurst-Kennedy J, Denison TA, Schwartz Z, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] controls growth plate development by inhibiting apoptosis in the reserve zone and stimulating response to 1alpha,25(OH)2D3 in hypertrophic cells, The Journal of steroid biochemistry and molecular biology, 121 (2010) 212– 216. 20307662

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    • cites [62] Boyan BD, Hyzy SL, Pan Q, Scott KM, Coutts RD, Healey R, Schwartz Z, 24R,25Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats, PLoS One, 11 (2016) e0161782. 27575371 PMC5019362

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    • cites [63] Tuohimaa P, Wang JH, Khan S, Kuuslahti M, Qian K, Manninen T, Auvinen P, Vihinen M, Lou YR, Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites, PLoS One, 8 (2013) e75338. 24116037 PMC3792969

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  • May combine two claims.

    Premisenone given

    24R,25(OH)2D3 is the first product of CYP24A1-catalyzed C24-oxidation of 25(OH)D3 and appears to have a physiological role.

    “One metabolite of note that appears to have a physiological role is 24R,25(OH)2D3, the first product in the C24-oxidation pathway of 25(OH)D3 metabolism catalyzed by CYP24A1 (Figs 2 and 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    A minor human pathway catalyzed by CYP24A1 begins with hydroxylation at C23 and is called the C23-oxidation pathway.

    “A minor pathway in humans, also catalyzed by CYP24A1, involves initial hydroxylation at C23 and is therefore known as the C23-oxidation pathway.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mass spectrometry alone cannot distinguish different monohydroxyvitamin D3 isomers because they share masses and generally show the same transitions, with water loss being the most common transition.

    “Thus, mass spectrometry itself does not distinguish between the different monohydroxyvitamin D3 isomers [11, 76, 77].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Herrmann M, Farrell CL, Pusceddu I, Fabregat-Cabello N, Cavalier E, Assessment of vitamin D status - a changing landscape, Clin Chem Lab Med, 55 (2017) 3– 26. 27362963

      Not checked in the free run.

    • cites [76] Higashi T, Shimada K, Toyo’oka T, Advances in determination of vitamin D related compounds in biological samples using liquid chromatography-mass spectrometry: a review, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 878 (2010) 1654– 1661. 19962356

      Not checked in the free run.

    • cites [77] El-Khoury JM, Reineks EZ, Wang S, Progress of liquid chromatography-mass spectrometry in measurement of vitamin D metabolites and analogues, Clinical biochemistry, 44 (2011) 66– 76. 20493831

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1α,25(OH)2D3 regulates global metabolic and endocrine homeostasis, endocrine organ function, and the cardiovascular system.

    “It is involved in the regulation of global metabolic and endocrine homeostasis and the functions of different endocrine organs, as well as in the functioning of the cardiovascular system [2, 6, 29, 46–50].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [2] Wacker M, Holick MF, Sunlight and Vitamin D: A global perspective for health, Dermatoendocrinol, 5 (2013) 51– 108. 24494042 PMC3897598 source

      Not checked in the free run.

    • cites [6] Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G, Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects, Physiol Rev, 96 (2016) 365– 408. 26681795 PMC4839493

      Not checked in the free run.

    • cites [29] Plum LA, DeLuca HF, Vitamin D, disease and therapeutic opportunities, Nat Rev Drug Discov, 9 (2010) 941– 955. 21119732

      Not checked in the free run.

    • cites [46] Welsh J, Function of the vitamin D endocrine system in mammary gland and breast cancer, Mol Cell Endocrinol, 453 (2017) 88– 95. 28579119 PMC5538720

      Not checked in the free run.

    • cites [47] Angellotti E, Pittas AG, The Role of Vitamin D in the Prevention of Type 2 Diabetes: To D or Not to D?, Endocrinology, 158 (2017) 2013– 2021. 28486616 PMC5505219

      Not checked in the free run.

    • cites [48] Dimova R, Tankova T, Chakarova N, Vitamin D in the Spectrum of Prediabetes and Cardiovascular Autonomic Dysfunction, J Nutr, 147 (2017) 1607– 1615. 28768837

      Not checked in the free run.

    • cites [49] Berridge MJ, Vitamin D deficiency and diabetes, Biochem J, 474 (2017) 1321– 1332. 28341729

      Not checked in the free run.

    • cites [50] Kassi E, Nasiri-Ansari N, Papavassiliou AG, Vitamin D affects glucocorticoid action in target cells, Oncotarget, 8 (2017) 7220– 7221. 28045677 PMC5352312

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In skin, 1α,25(OH)2D3 supports epidermal barrier formation and hair cycling and has photoprotective and ameliorating effects on skin cancer and proliferative and inflammatory cutaneous diseases.

    “In the skin, it plays an important role in the formation of the epidermal barrier and hair cycling. It also has photoprotective properties and has a wide variety of ameliorating effects on skin cancer and on proliferative and inflammatory cutaneous diseases [1, 3, 30, 31, 54–59].”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [1] Holick MF, Vitamin D deficiency N Engl J Med, 357 (2007) 266– 281. 17634462 source

      Not checked in the free run.

    • cites [3] Holick MF, Vitamin D: A millenium perspective, Journal of cellular biochemistry, 88 (2003) 296– 307. 12520530 source

      Not checked in the free run.

    • cites [30] Mason RS, Reichrath J, Sunlight vitamin D and skin cancer, Anti-cancer agents in medicinal chemistry, 13 (2013) 83– 97. 23094924

      Not checked in the free run.

    • cites [31] Bikle DD, Elalieh H, Welsh J, Oh D, Cleaver J, Teichert A, Protective role of vitamin D signaling in skin cancer formation, J Steroid Biochem Mol Biol, 136 (2013) 271– 279. 23059470 PMC3596439

      Not checked in the free run.

    • cites [54] Bikle DD, Vitamin D receptor, UVR, and skin cancer: a potential protective mechanism, J Invest Dermatol, 128 (2008) 2357– 2361. 18787544 PMC9017605

      Not checked in the free run.

    • cites [55] Elias PM, Structure and function of the stratum corneum extracellular matrix, J Invest Dermatol, 132 (2012) 2131– 2133. 22895445 PMC3587970

      Not checked in the free run.

    • cites [56] Trojanowska M, Cellular and molecular aspects of vascular dysfunction in systemic sclerosis, Nature reviews. Rheumatology, 6 (2010) 453– 460. 20585340 PMC3824624

      Not checked in the free run.

    • cites [57] Dixon KM, Norman AW, Sequeira VB, Mohan R, Rybchyn MS, Reeve VE, Halliday GM, Mason RS, 1alpha,25(OH)(2)-vitamin D and a nongenomic vitamin D analogue inhibit ultraviolet radiation-induced skin carcinogenesis, Cancer Prev Res (Phila), 4 (2011) 1485– 1494. 21733837

      Not checked in the free run.

    • cites [58] Makarova A, Wang G, Dolorito JA, Kc S, Libove E, Epstein EH Jr., Vitamin D3 Produced by Skin Exposure to UVR Inhibits Murine Basal Cell Carcinoma Carcinogenesis, J Invest Dermatol, 137 (2017) 2613– 2619. 28774592

      Not checked in the free run.

    • cites [59] Slominski AT, Zmijewski MA, Semak I, Zbytek B, Pisarchik A, Li W, Zjawiony J, Tuckey RC, Cytochromes p450 and skin cancer: role of local endocrine pathways, Anticancer Agents Med Chem, 14 (2014) 77– 96. 23869782 PMC3740756

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    1α,25(OH)2D3 is important in neurodevelopment and in the adult central and peripheral nervous system.

    “1α,25(OH)2D3 is also important in neurodevelopment as well as in the functioning of the adult central and peripheral nervous system [38, 44, 45].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Berridge MJ, Vitamin D deficiency: infertility and neurodevelopmental diseases (attention deficit hyperactivity disorder, autism, and schizophrenia), Am J Physiol Cell Physiol, 314 (2018) C135– C151. 29070492

      Not checked in the free run.

    • cites [44] Cui X, Gooch H, Petty A, McGrath JJ, Eyles D, Vitamin D and the brain: Genomic and nongenomic actions, Mol Cell Endocrinol, 453 (2017) 131– 143. 28579120

      Not checked in the free run.

    • cites [45] Di Somma C, Scarano E, Barrea L, Zhukouskaya VV, Savastano S, Mele C, Scacchi M, Aimaretti G, Colao A, Marzullo P, Vitamin D and Neurological Diseases: An Endocrine View, Int J Mol Sci, 18 (2017). PMC5713448 29160835

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP27B1 is expressed at highest levels in kidney, placenta and disease-activated macrophages, and at lower levels in many other tissues, suggesting local production of 1α,25(OH)2D3 for intercrine actions.

    “CYP27B1 is expressed at highest levels in the kidney, placenta and disease-activated macrophages but is also expressed in many other tissues at lower levels, suggesting local production of 1α,25(OH)2D3 for intercrine actions [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Adams JS, Hewison M, Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase, Archives of biochemistry and biophysics, 523 (2012) 95– 102. 22446158 PMC3361592

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CYP11A1 catalyzes cleavage of the cholesterol side chain and is the most studied mitochondrial CYP.

    “CYP11A1 (also known as cytochrome P450scc), catalyzes the cleavage of the side chain of cholesterol and is the most studied of the mitochondrial CYPs [65, 81].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, Tuckey RC, Novel activities of CYP11A1 and their potential physiological significance, The Journal of steroid biochemistry and molecular biology, 151 (2015) 25– 37. 25448732 PMC4757911 source

      Not checked in the free run.

    • cites [81] Miller WL, Auchus RJ, The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders, Endocr Rev, 32 (2011) 81– 151. 21051590 PMC3365799 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    25(OH)D3 adopts a similar pose to 1α,25(OH)2D3 in the VDR active site but has much lower affinity.

    “25(OH)D3 adopts a similar pose to 1α,25(OH)2D3 in the active site of the VDR [131] but has much lower affinity [133].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Lou YR, Molnar F, Perakyla M, Qiao S, Kalueff AV, St-Arnaud R, Carlberg C, Tuohimaa P, 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand, The Journal of steroid biochemistry and molecular biology, 118 (2010) 162– 170. 19944755

      Not checked in the free run.

    • cites [133] Bouillon R, Okamura WH, Norman AW, Structure-function relationships in the vitamin D endocrine system, Endocr Rev, 16 (1995) 200– 257. 7781594

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a UK cohort of 32 healthy individuals, mean serum 25(OH)D2 was 18 nM and mean 25(OH)D3 was 28 nM.

    “In the study by Shah and coworkers [125] of a United Kingdom cohort of 32 healthy individuals, the mean serum 25(OH)D2 concentration was 18 nM compared to 28 nM for 25(OH)D3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Shah I, Petroczi A, Naughton DP, Exploring the role of vitamin D in type 1 diabetes, rheumatoid arthritis, and Alzheimer disease: new insights from accurate analysis of 10 forms, The Journal of clinical endocrinology and metabolism, 99 (2014) 808– 816. 24423328

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent evidence suggests that 25(OH)D3 has biological activity in its own right at high concentrations and may contribute to vitamin D toxicity.

    “Although generally considered to be an inactive precursor to 1α,25(OH)2D3, some recent evidence suggests that it has biological activity in its own right at high concentrations that may be responsible for vitamin D toxicity [16, 63, 131, 132].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [16] Khanal R, Nemere I, Membrane receptors for vitamin D metabolites, Crit Rev Eukaryot Gene Expr, 17 (2007) 31– 47. 17341182

      Not checked in the free run.

    • cites [63] Tuohimaa P, Wang JH, Khan S, Kuuslahti M, Qian K, Manninen T, Auvinen P, Vihinen M, Lou YR, Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites, PLoS One, 8 (2013) e75338. 24116037 PMC3792969

      Not checked in the free run.

    • cites [131] Lou YR, Molnar F, Perakyla M, Qiao S, Kalueff AV, St-Arnaud R, Carlberg C, Tuohimaa P, 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand, The Journal of steroid biochemistry and molecular biology, 118 (2010) 162– 170. 19944755

      Not checked in the free run.

    • cites [132] Deluca HF, Prahl JM, Plum LA, 1,25-Dihydroxyvitamin D is not responsible for toxicity caused by vitamin D or 25-hydroxyvitamin D, Archives of biochemistry and biophysics, 505 (2011) 226– 230. 20965147

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    25(OH)D3 is the major circulating form of vitamin D3 and is commonly used to monitor vitamin D status.

    “25(OH)D3 is the major circulating form of vitamin D3 in the bloodstream and is commonly used to monitor vitamin D status.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    25(OH)D3 is primarily produced in the liver by CYP2R1 acting on circulating vitamin D3, although other CYP enzymes including CYP27A1 can also catalyze this reaction.

    “It is primarily produced in the liver by the action of CYP2R1 on circulating vitamin D3 (Fig. 2) although other CYP enzymes in the liver including CYP27A1 can also catalyze this reaction [4, 93, 123].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Zhu J, DeLuca HF, Vitamin D 25-hydroxylase - Four decades of searching, are we there yet?, Archives of biochemistry and biophysics, 523 (2012) 30– 36. 22310641

      Not checked in the free run.

    • cites [93] Cheng CYS, Kim TK, Jeayeng S, Slominski AT, Tuckey RC, Properties of Purified CYP2R1 in a Reconstituted Membrane Environment and its 25-Hydroxylation of 20-Hydroxyvitamin D3, The Journal of steroid biochemistry and molecular biology, 177 (2018) 59– 69. 28716760 PMC5767547

      Not checked in the free run.

    • cites [123] Sawada N, Sakaki T, Ohta M, Inouye K, Metabolism of vitamin D(3) by human CYP27A1, Biochemical and biophysical research communications, 273 (2000) 977– 984. 10891358

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1α,25(OH)2D is reported in serum at 50-150 pM, almost 1000 times lower than 25(OH)D3.

    “The major hormonally active form of vitamin D, 1α,25(OH)2D, is reported to be in serum in the range of 50 to 150 pM, as measured by a competitive binding assay following HPLC [135], which is almost 1000 times lower than 25(OH)D3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Lips P, Relative value of 25(OH)D and 1,25(OH)2D measurements, Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research, 22 (2007) 1668– 1671. 17645404

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using an LC/MS/MS assay, 1α,25(OH)2D3 had a mean serum concentration of 28 pM in 32 healthy individuals, while 1α,25(OH)2D2 was higher at 170 pM.

    “Using an LC/MS/MS assay which could distinguish between the D2 and D3 forms of 1α,25(OH)2D, 1α,25(OH)2D3 was reported to be in serum at a mean concentration of 28 pM in 32 healthy individuals. 1α,25(OH)2D2 was higher for this cohort at 170 pM, [125], indicative of dietary D2 supplementation (Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Shah I, Petroczi A, Naughton DP, Exploring the role of vitamin D in type 1 diabetes, rheumatoid arthritis, and Alzheimer disease: new insights from accurate analysis of 10 forms, The Journal of clinical endocrinology and metabolism, 99 (2014) 808– 816. 24423328

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CYP11A1 is expressed at high levels in adrenal cortex, gonads and placenta and at lower levels in several other tissues including brain, skin and gut.

    “CYP11A1 is expressed at high levels in the adrenal cortex, gonads and placenta and at lower levels in several other tissues including the brain, skin and gut [115].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Slominski A, Zbytek B, Nikolakis G, Manna PR, Skobowiat C, Zmijewski M, Li W, Janjetovic Z, Postlethwaite A, Zouboulis CC, Tuckey RC, Steroidogenesis in the skin: implications for local immune functions, The Journal of steroid biochemistry and molecular biology, 137 (2013) 107– 123. 23435015 PMC3674137 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single enzyme, CYP24A1, can catalyze all oxidation steps from 1α,25(OH)2D3 to 24-oxo-1,23S,25(OH)3D3 and calcitroic acid, with similar reactions converting 25(OH)D3 to 23(OH)-24,25,26,27-tetranor D3.

    “Expression of the rat enzyme in E. coli and activity assays using the membrane fraction demonstrated that a single enzyme, CYP24A1, could catalyze all the oxidation steps from 1α,25(OH)2D3 through to 24-oxo1,23S,25(OH)3D3 and calcitroic acid (Fig. 3), with similar reactions for conversion of 25(OH)D3 through to 23(OH)- 24,25,26,27-tetranor D3 [107, 108].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] Akiyoshi-Shibata M, Sakaki T, Ohyama Y, Noshiro M, Okuda K, Yabusaki Y, Further oxidation of hydroxycalcidiol by calcidiol 24-hydroxylase. A study with the mature enzyme expressed in Escherichia coli, European journal of biochemistry, 224 (1994) 335– 343. 7925346

      Not checked in the free run.

    • cites [108] Sakaki T, Sawada N, Nonaka Y, Ohyama Y, Inouye K, Metabolic studies using recombinant escherichia coli cells producing rat mitochondrial CYP24 CYP24 can convert 1alpha,25-dihydroxyvitamin D3 to calcitroic acid, European journal of biochemistry, 262 (1999) 43– 48. 10231362

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP2R1 acts as a 25-hydroxylase on both vitamins D3 and D2, whereas CYP27A1 cannot hydroxylate vitamin D2 at C25.

    “This revealed that unlike CYP27A1which cannot hydroxylate vitamin D2 at C25 [87], it acted as a 25-hydroxylase on both vitamins D3 and D2 [92].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Guo YD, Strugnell S, Back DW, Jones G, Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions, Proceedings of the National Academy of Sciences of the United States of America, 90 (1993) 8668– 8672. 7690968 PMC47419

      Not checked in the free run.

    • cites [92] Shinkyo R, Sakaki T, Kamakura M, Ohta M, Inouye K, Metabolism of vitamin D by human microsomal CYP2R1, Biochemical and biophysical research communications, 324 (2004) 451457. 15465040

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Cyp27b1-knockout cultured mouse skin fibroblasts, 500 nM 25(OH)D3 regulated many but not all genes regulated by 1α,25(OH)2D3, plus over 100 distinct genes.

    “In cultured mouse skin fibroblasts in which Cyp27b1 had been knocked out (preventing conversion of 25(OH)D3 to 1α,25(OH)2D3), 25(OH)D3 (500 nM) regulated many but not all of the same genes regulated by 1α,25(OH)2D3, plus over 100 genes distinct from those regulated by 1α,25(OH)2D3 [63].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Tuohimaa P, Wang JH, Khan S, Kuuslahti M, Qian K, Manninen T, Auvinen P, Vihinen M, Lou YR, Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites, PLoS One, 8 (2013) e75338. 24116037 PMC3792969

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum 25(OH)D2 levels are low and variable depending on dietary D2 intake, with wild mushrooms a major source, or on vitamin D2 supplementation.

    “Serum levels of 25(OH)D2 are low and variable depending on the amount of D2 in the diet with wild mushrooms being a major source, or whether a vitamin D2 supplement is taken [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Holick MF, Vitamin D deficiency N Engl J Med, 357 (2007) 266– 281. 17634462 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum 3-epi-25(OH)D3 varies widely, reported from below 1% to 25% of 25(OH)D3, with an average of 4.75% in one study and similar values in others.

    “The concentration of 3-epi-25(OH)D3 in serum varies greatly and has been reported to range from below 1% up to 25% of that of 25(OH)D3 with an average of 4.75% in one study [138] and similar values in others [139, 140] (Table 2).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [138] Lensmeyer G, Poquette M, Wiebe D, Binkley N, The C-3 epimer of 25-hydroxyvitamin D(3) is present in adult serum, The Journal of clinical endocrinology and metabolism, 97 (2012) 163– 168. 22013102

      Not checked in the free run.

    • cites [139] Baecher S, Leinenbach A, Wright JA, Pongratz S, Kobold U, Thiele R, Simultaneous quantification of four vitamin D metabolites in human serum using high performance liquid chromatography tandem mass spectrometry for vitamin D profiling, Clinical biochemistry, 45 (2012) 1491– 1496. 22771503

      Not checked in the free run.

    • cites [140] Clarke MW, Tuckey RC, Gorman S, Holt B, Hart PH, Optimized 25-hydroxyvitamin D analysis using liquid–liquid extraction with 2D separation with LC/MS/MS detection, provides superior precision compared to conventional assays, Metabolomics, 9 (2013) 1031– 1040.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The gene encoding 25-hydroxyvitamin D3 3-epimerase has not been identified.

    “It is poorly characterized and surprisingly the gene encoding it has not been identified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    3-Epi-25(OH)D3 and 3-epi-25(OH)D2 have a 3α-hydroxyl group instead of the 3β-hydroxyl group of 25(OH)D3 and 25(OH)D2 and are produced by 25-hydroxyvitamin D3 3-epimerase.

    “3-Epi-25(OH)D3 and 3-epi-25(OH)D2 have a 3α-hydroxyl group rather than the 3β-hydroxyl group present in 25(OH)D3 and 25(OH)D2, respectively (Fig. 2), and are produced by 25-hydroxyvitamin D3 3-epimerase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    25(OH)D3 3-epimerase uses NADPH as a cofactor for 3β→3α epimerization and can also epimerize 1α,25(OH)2D3 and 24R,25(OH)2D3, though more slowly than 25(OH)D3.

    “Measurements of 25(OH)D3–3-epimerase activity in microsomes prepared from osteoblastic UMR-106 cells indicate that it uses NADPH as cofactor for the 3β → 3α epimerization, and can also catalyze the epimerization of 1α,25(OH)2D3 and 24R,25(OH)2D3, although at lower rate than for 25(OH)D3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    3-Epi-1α,25(OH)2D3 binds VDR with 35- to 120-fold lower affinity than 1α,25(OH)2D3 and has markedly reduced ability to stimulate intestinal calcium absorption.

    “It binds to the VDR with 35- to 120-fold lower affinity than 1α,25(OH)2D3 and has markedly reduced ability to stimulate intestinal calcium absorption [73–75].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [73] Masuda S, Kamao M, Schroeder NJ, Makin HL, Jones G, Kremer R, Rhim J, Okano T, Characterization of 3-epi-1alpha,25-dihydroxyvitamin D3 involved in 1alpha,25dihydroxyvitamin D3 metabolic pathway in cultured cell lines, Biol Pharm Bull, 23 (2000) 133139. 10706373

      Not checked in the free run.

    • cites [74] Norman AW, Bouillon R, Farach-Carson MC, Bishop JE, Zhou LX, Nemere I, Zhao J, Muralidharan KR, Okamura WH, Demonstration that 1 beta,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1 alpha,25-dihydroxyvitamin D3, The Journal of biological chemistry, 268 (1993) 20022– 20030. 8397195

      Not checked in the free run.

    • cites [75] Nakagawa K, Sowa Y, Kurobe M, Ozono K, Siu-Caldera ML, Reddy GS, Uskokovic MR, Okano T, Differential activities of 1alpha,25-dihydroxy-16-ene-vitamin D(3) analogs and their 3epimers on human promyelocytic leukemia (HL-60) cell differentiation and apoptosis, Steroids, 66 (2001) 327– 337. 11179741

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 3β→3α epimerization reaction is reported to be irreversible.

    “The reaction is reported to be irreversible [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Kamao M, Hatakeyama S, Sakaki T, Sawada N, Inouye K, Kubodera N, Reddy GS, Okano T, Measurement and characterization of C-3 epimerization activity toward vitamin D3, Archives of biochemistry and biophysics, 436 (2005) 196– 205. 15752725

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    3-Epi-25(OH)D3 has higher ionization efficiency than 25(OH)D3 in LC/MS/MS with electrospray ionization, causing overestimation of its contribution when the two epimers are not separated.

    “Additionally, 3-epi-25(OH)D3 displays a higher ionization efficiency than 25(OH)D3 in LC/MS/MS with electrospray ionization, resulting in an overestimation of the contribution of 3-epi-25(OH)D3 in procedures that do not separate the two epimers [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] van den Ouweland JM, Beijers AM, van Daal H, Overestimation of 25-hydroxyvitamin D3 by increased ionisation efficiency of 3-epi-25-hydroxyvitamin D3 in LC-MS/MS methods not separating both metabolites as determined by an LC-MS/MS method for separate quantification of 25-hydroxyvitamin D3, 3-epi-25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human serum, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 967 (2014) 195– 202. 25125396

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    25-Hydroxyvitamin D3 3-epimerase is present in the endoplasmic reticulum of liver, bone and skin cells but not kidney.

    “This enzyme is present in the endoplasmic reticulum of a range of cells/tissues including liver, bone and skin [72, 136], but not kidney [137].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [72] Kamao M, Hatakeyama S, Sakaki T, Sawada N, Inouye K, Kubodera N, Reddy GS, Okano T, Measurement and characterization of C-3 epimerization activity toward vitamin D3, Archives of biochemistry and biophysics, 436 (2005) 196– 205. 15752725

      Not checked in the free run.

    • cites [136] Astecker N, Reddy GS, Herzig G, Vorisek G, Schuster I, 1alpha,25-Dihydroxy-3-epivitamin D3 a physiological metabolite of 1alpha,25-dihydroxyvitamin D3: its production and metabolism in primary human keratinocytes, Molecular and cellular endocrinology, 170 (2000) 91– 101. 11162893

      Not checked in the free run.

    • cites [137] Siu-Caldera ML, Sekimoto H, Weiskopf A, Vouros P, Muralidharan KR, Okamura WH, Bishop J, Norman AW, Uskokovic MR, Schuster I, Reddy GS, Production of 1alpha,25dihydroxy-3-epi-vitamin D3 in two rat osteosarcoma cell lines (UMR 106 and ROS 17/2.8): existence of the C-3 epimerization pathway in ROS 17/2.8 cells in which the C-24 oxidation pathway is not expressed, Bone, 24 (1999) 457– 463. 10321905

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    21,25(OH)2D3 is present in blood of pigs given high-dose vitamin D3.

    “21,25(OH)2D3 is present in the blood of pigs given a high dose of vitamin D3 [156]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Suda T, DeLuca HF, Schnoes HK, Ponchon G, Tanaka Y, Holick MF, 21,25dihydroxycholecalciferol. A metabolite of vitamin D3 preferentially active on bone, Biochemistry, 9 (1970) 2917– 2922. 4318898

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    1β,25(OH)2D3 concentration is similar in kidney failure patients, suggesting it is not produced by CYP27B1 but by an unidentified enzyme acting on 25(OH)D3.

    “Its concentration was similar in patients with kidney failure suggesting that it does not arise from the action of CYP27B1, but rather from an unidentified enzyme acting directly on 25(OH)D3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Pauwels S, Jans I, Billen J, Heijboer A, Verstuyf A, Carmeliet G, Mathieu C, Maestro M, Waelkens E, Evenepoel P, Bouillon R, Vanderschueren D, Vermeersch P, 1beta,25-Dihydroxyvitamin D3: A new vitamin D metabolite in human serum, The Journal of steroid biochemistry and molecular biology, (2017). 28193495

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CYP3A4 in liver microsomes can produce 25,26(OH)2D3 from 25(OH)D3.

    “It has been reported that 25,26(OH)2D3 can be produced by the action of CYP3A4 on 25(OH)D3 in liver microsomes [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Wang Z, Lin YS, Zheng XE, Senn T, Hashizume T, Scian M, Dickmann LJ, Nelson SD, Baillie TA, Hebert MF, Blough D, Davis CL, Thummel KE, An inducible cytochrome P450 3A4dependent vitamin D catabolic pathway, Molecular pharmacology, 81 (2012) 498– 509. 22205755 PMC3310418

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    25,26(OH)2D3 was among the first 25(OH)D3 metabolites identified in plasma.

    “one of the first metabolites of 25(OH)D3 identified in plasma was 25,26(OH)2D3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Shepard RM, Horst RL, Hamstra AJ, DeLuca HF, Determination of vitamin D and its metabolites in plasma from normal and anephric man, The Biochemical journal, 182 (1979) 5569. PMC1161234 227368

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP24A1 produces 24R,25(OH)2D3 mainly in the kidney and also in vitamin D target tissues.

    “24R,25(OH)2D3 is produced by the action of CYP24A1 (Fig. 2), primarily in the kidney but also in vitamin D target tissues [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Jones G, Prosser DE, Kaufmann M, 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D, Archives of biochemistry and biophysics, 523 (2012) 9– 18. 22100522

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    25,26(OH)2D3 concentration was reported as 1.75 nM by competitive binding assay.

    “Its concentration was reported to be 1.75 nM using a competitive binding assay [148]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Shepard RM, Horst RL, Hamstra AJ, DeLuca HF, Determination of vitamin D and its metabolites in plasma from normal and anephric man, The Biochemical journal, 182 (1979) 5569. PMC1161234 227368

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    23S,25(OH)2D3 is reasonably predicted to be present in human serum, produced with 24R,25(OH)2D3 in a 1:4 ratio by human CYP24A1.

    “could reasonably be predicted to be present in human serum, being produced in the ratio 1:4 with 24R,25(OH)2D3 by human CYP24A1 [112, 113]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Sakaki T, Sawada N, Komai K, Shiozawa S, Yamada S, Yamamoto K, Ohyama Y, Inouye K, Dual metabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24, European journal of biochemistry, 267 (2000) 6158– 6165. 11012668

      Not checked in the free run.

    • cites [113] Tieu EW, Tang EK, Tuckey RC, Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway, The FEBS journal, 281 (2014) 3280– 3296. 24893882

      Not checked in the free run.

    • Rests on an assumption: Enzyme activities observed in vitro or in animal models predict the presence and metabolism of the same vitamin D metabolites in human serum.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    25,26(OH)2D3 is half as effective as 25(OH)D3 at stimulating intestinal calcium transport.

    “was half as effective as 25(OH)D3 at stimulating intestinal calcium transport [156]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Suda T, DeLuca HF, Schnoes HK, Ponchon G, Tanaka Y, Holick MF, 21,25dihydroxycholecalciferol. A metabolite of vitamin D3 preferentially active on bone, Biochemistry, 9 (1970) 2917– 2922. 4318898

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    25,26(OH)2D3 is the 25R,26(OH)2D3 epimer.

    “but was later reported to be the 25R,26(OH)2D3 epimer [159]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Redel J, Bazely N, Tanaka Y, DeLuca HF, The absolute configuration of the natural 25,26dihydroxycholecalciferol, FEBS letters, 94 (1978) 228– 230. 700144

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1β,25(OH)2D3 is a poor agonist at the VDR genomic binding site but a good antagonist of non-genomic actions of 1α,25(OH)2D3 such as rapid intestinal calcium transport.

    “It has previously been shown to be a poor agonist for the genomic binding site on the VDR but a good antagonist of the non-genomic actions of 1α,25(OH)2D3 such as the rapid stimulation of calcium transport by the intestine [74, 163, 164].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Norman AW, Bouillon R, Farach-Carson MC, Bishop JE, Zhou LX, Nemere I, Zhao J, Muralidharan KR, Okamura WH, Demonstration that 1 beta,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1 alpha,25-dihydroxyvitamin D3, The Journal of biological chemistry, 268 (1993) 20022– 20030. 8397195

      Not checked in the free run.

    • cites [163] Norman AW, Nemere I, Muralidharan KR, Okamura WH, 1 beta, 25 (OH)2-vitamin D3 is an antagonist of 1 alpha,25 (OH)2-vitamin D3 stimulated transcaltachia (the rapid hormonal stimulation of intestinal calcium transport), Biochemical and biophysical research communications, 189 (1992) 1450– 1456. 1336368

      Not checked in the free run.

    • cites [164] Baran DT, Ray R, Sorensen AM, Honeyman T, Holick MF, Binding characteristics of a membrane receptor that recognizes 1 alpha,25-dihydroxyvitamin D3 and its epimer, 1 beta,25dihydroxyvitamin D3, Journal of cellular biochemistry, 56 (1994) 510– 517. 7890809

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    24R,25(OH)2D3 stimulates growth plate development and bone-fracture repair.

    “stimulating growth plate development and bone-fracture repair, as described in Section 1.3 [19, 60–64]”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [19] St-Arnaud R, Naja RP, Vitamin D metabolism, cartilage and bone fracture repair, Molecular and cellular endocrinology, 347 (2011) 48– 54. 21664253

      Not checked in the free run.

    • cites [60] St-Arnaud R, CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24, The Journal of steroid biochemistry and molecular biology, 121 (2010) 254– 256. 20144713

      Not checked in the free run.

    • cites [61] Boyan BD, Hurst-Kennedy J, Denison TA, Schwartz Z, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] controls growth plate development by inhibiting apoptosis in the reserve zone and stimulating response to 1alpha,25(OH)2D3 in hypertrophic cells, The Journal of steroid biochemistry and molecular biology, 121 (2010) 212– 216. 20307662

      Not checked in the free run.

    • cites [62] Boyan BD, Hyzy SL, Pan Q, Scott KM, Coutts RD, Healey R, Schwartz Z, 24R,25Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats, PLoS One, 11 (2016) e0161782. 27575371 PMC5019362

      Not checked in the free run.

    • cites [63] Tuohimaa P, Wang JH, Khan S, Kuuslahti M, Qian K, Manninen T, Auvinen P, Vihinen M, Lou YR, Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites, PLoS One, 8 (2013) e75338. 24116037 PMC3792969

      Not checked in the free run.

    • cites [64] Martineau C, Naja RP, Husseini A, Hamade B, Kaufmann M, Akhouayri O, Arabian A, Jones G, St-Arnaud R, Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2, The Journal of clinical investigation, 128 (2018) 3546– 3557. 30010626 PMC6063485

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1β,25(OH)2D3 concentration is 26 pM in healthy subjects, range 7-46 pM, with a 1β/1α ratio of 0.05-0.44.

    “Its concentration was reported to be 26 pM in healthy subjects (range 7–46 pM), with the 1β/1α ratio ranging from 0.05–0.44.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Pauwels S, Jans I, Billen J, Heijboer A, Verstuyf A, Carmeliet G, Mathieu C, Maestro M, Waelkens E, Evenepoel P, Bouillon R, Vanderschueren D, Vermeersch P, 1beta,25-Dihydroxyvitamin D3: A new vitamin D metabolite in human serum, The Journal of steroid biochemistry and molecular biology, (2017). 28193495

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 3-monoglucuronide of vitamin D3 is present in bile.

    “The 3-monoglucuronide of vitamin D3 itself has been reported to be present in bile [172]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Kumar R, The metabolism and mechanism of action of 1,25-dihydroxyvitamin D3, Kidney Int, 30 (1986) 793– 803. 3029498

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    25(OH)D3-3-sulfate is a major vitamin D3 form in human serum, with a mean of 46 nM in 10 healthy individuals.

    “25-Hydroxyvitamin D3–3-sulfate (25(OH)D3–3-sulfate) has been identified as a major form of vitamin D3 in human serum with the first quantitative measurement on 10 healthy individuals giving a mean serum concentration of 46 nM [165].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Axelson M, 25-Hydroxyvitamin D3 3-sulphate is a major circulating form of vitamin D in man, FEBS letters, 191 (1985) 171– 175. 4054307

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    25(OH)D3-3-glucuronide was measured in serum of six healthy volunteers at a mean of 3.4 nM, with 25(OH)D3-3-sulfate at 55.6 nM.

    “The reported mean concentration of 25(OH)D3–3-glucuronide was 3.4 nM with 25(OH)D3–3-sulfate being 55.6 nM [171].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Gao C, Bergagnini-Kolev MC, Liao MZ, Wang Z, Wong T, Calamia JC, Lin YS, Mao Q, Thummel KE, Simultaneous quantification of 25-hydroxyvitamin D3–3-sulfate and 25hydroxyvitamin D3–3-glucuronide in human serum and plasma using liquid chromatographytandem mass spectrometry coupled with DAPTAD-derivatization, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1060 (2017) 158– 165. 28622619 PMC5585037

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytosol from human liver and small intestine can 3-sulfate 25(OH)D3, with SULT2A1 as the major sulfotransferase.

    “The cytosol from several human tissues including liver and small intestine can catalyze the 3sulfation of 25(OH)D3, with SULT2A1 identified as the major sulfotransferase involved [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Kurogi K, Sakakibara Y, Suiko M, Liu MC, Sulfation of vitamin D3 -related compounds: Identification and characterization of the responsible human cytosolic sulfotransferases, FEBS letters, (2017). 28746983

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Hydrolysis and activation of 25(OH)D3-3-sulfate to 1α,25(OH)2D3 are likely necessary for its biological activity.

    “It is likely that its hydrolysis and activation to 1α,25(OH)2D3 are necessary for any biological activity”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These novel secosteroids lacking C1α-hydroxyl are noncalcemic, while 1α,20S(OH)2D3 has low calcemic activity.

    “These novel secosteroids lacking the C1α-hydroxyl group are noncalcemic, while 1α,20S(OH)2D3 displays low calcemic activity [68–70, 175].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [68] Wang J, Slominski A, Tuckey RC, Janjetovic Z, Kulkarni A, Chen J, Postlethwaite AE, Miller D, Li W, 20-hydroxyvitamin D(3) inhibits proliferation of cancer cells with high efficacy while being non-toxic, Anticancer Res, 32 (2012) 739– 746. 22399586 PMC3312810

      Not checked in the free run.

    • cites [69] Slominski AT, Janjetovic Z, Fuller BE, Zmijewski MA, Tuckey RC, Nguyen MN, Sweatman T, Li W, Zjawiony J, Miller D, Chen TC, Lozanski G, Holick MF, Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity, PLoS One, 5 (2010) e9907. 20360850 PMC2845617 source

      Not checked in the free run.

    • cites [70] Chen J, Wang J, Kim TK, Tieu EW, Tang EK, Lin Z, Kovacic D, Miller DD, Postlethwaite A, Tuckey RC, Slominski AT, Li W, Novel vitamin D analogs as potential therapeutics: metabolism, toxicity profiling, and antiproliferative activity, Anticancer Res, 34 (2014) 2153– 2163. 24778017 PMC4015637

      Not checked in the free run.

    • cites [175] Slominski A, Janjetovic Z, Tuckey RC, Nguyen MN, Bhattacharya KG, Wang J, Li W, Jiao Y, Gu W, Brown M, Postlethwaite AE, 20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo, The Journal of clinical endocrinology and metabolism, 98 (2013) E298– 303. 23295467 PMC3565109 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Because CYP11A1-derived secosteroids require neither CYP2R1 nor CYP27B1, their level regulation may differ from 25(OH)D3 or 1α,25(OH)2D3.

    “because these secosteroids are made by CYP11A1 and require neither CYP2R1 nor CYP27B1 for their synthesis, regulation of their levels may be very different to that for 25(OH)D3 or 1α,25(OH)2D3”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These secosteroids have cell-type-dependent phenotypic effects secondary to binding VDR and/or RORα and γ as reverse agonists.

    “They also express diverse phenotypic effects dependent on cell type (reviewed in [52, 65, 66]) that are secondary to binding to either the VDR, and/or to RORα and γ on which they act as reverse agonists [20, 21, 67, 178–183].”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [20] Slominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, Wang J, Postlethwaite A, Li W, Tuckey RC, Jetten AM, RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23dihydroxyvitamin D, FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 28 (2014) 2775– 2789. 24668754 PMC4062828

      Not checked in the free run.

    • cites [21] Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, Li W, Tuckey RC, Jetten AM, Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORalpha and RORgamma, The Journal of steroid biochemistry and molecular biology, 173 (2017) 42– 56. 27693422 PMC5373926 source

      Not checked in the free run.

    • cites [67] Slominski AT, Kim TK, Li W, Yi AK, Postlethwaite A, Tuckey RC, The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions, The Journal of steroid biochemistry and molecular biology, 144PA (2014) 28– 39. PMC4002668 24176765 source

      Not checked in the free run.

    • cites [178] Janjetovic Z, Tuckey RC, Nguyen MN, Thorpe EM Jr., Slominski AT, 20,23dihydroxyvitamin D3, novel P450scc product, stimulates differentiation and inhibits proliferation and NF-kappaB activity in human keratinocytes, J Cell Physiol, 223 (2010) 36– 48. 20020487 PMC2814891 source

      Not checked in the free run.

    • cites [179] Zbytek B, Janjetovic Z, Tuckey RC, Zmijewski MA, Sweatman TW, Jones E, Nguyen MN, Slominski AT, 20-Hydroxyvitamin D3, a product of vitamin D3 hydroxylation by cytochrome P450scc, stimulates keratinocyte differentiation, J Invest Dermatol, 128 (2008) 2271– 2280. 18368131 PMC2574837 source

      Not checked in the free run.

    • cites [180] Slominski AT, Kim TK, Janjetovic Z, Tuckey RC, Bieniek R, Yue J, Li W, Chen J, Nguyen MN, Tang EK, Miller D, Chen TC, Holick M, 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells, Am J Physiol Cell Physiol, 300 (2011) C526– 541. 21160030 PMC3063966 source

      Not checked in the free run.

    • cites [181] Lin Z, Marepally SR, Goh ESY, Cheng CYS, Janjetovic Z, Kim TK, Miller DD, Postlethwaite AE, Slominski AT, Tuckey RC, Peluso-Iltis C, Rochel N, Li W, Investigation of 20Shydroxyvitamin D3 analogs and their 1alpha-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities, Sci Rep, 8 (2018) 1478. 29367669 PMC5784132

      Not checked in the free run.

    • cites [182] Lin Z, Chen H, Belorusova AY, Bollinger JC, Tang EKY, Janjetovic Z, Kim TK, Wu Z, Miller DD, Slominski AT, Postlethwaite AE, Tuckey RC, Rochel N, Li W, 1alpha,20SDihydroxyvitamin D3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis, Sci Rep, 7 (2017) 10193. 28860545 PMC5579064

      Not checked in the free run.

    • cites [183] Kim TK, Wang J, Janjetovic Z, Chen J, Tuckey RC, Nguyen MN, Tang EK, Miller D, Li W, Slominski AT, Correlation between secosteroid-induced vitamin D receptor activity in melanoma cells and computer-modeled receptor binding strength, Mol Cell Endocrinol, 361 (2012) 143– 152. 22546549 PMC3409337 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These secosteroids reduce skin fibrosis and rheumatoid arthritis symptoms and decrease UVB-induced DNA damage in rodents.

    “They are also active when administered to rodents, reducing the symptoms of skin fibrosis, rheumatoid arthritis and decreasing DNA damage caused by UVB irradiation [175–177].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [175] Slominski A, Janjetovic Z, Tuckey RC, Nguyen MN, Bhattacharya KG, Wang J, Li W, Jiao Y, Gu W, Brown M, Postlethwaite AE, 20S-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo, The Journal of clinical endocrinology and metabolism, 98 (2013) E298– 303. 23295467 PMC3565109 source

      Not checked in the free run.

    • cites [176] Tongkao-On W, Carter S, Reeve VE, Dixon KM, Gordon-Thomson C, Halliday GM, Tuckey RC, Mason RS, CYP11A1 in skin: an alternative route to photoprotection by vitamin D compounds, The Journal of steroid biochemistry and molecular biology, 148 (2015) 72– 78. 25448743 source

      Not checked in the free run.

    • cites [177] Skobowiat C, Oak AS, Kim TK, Yang CH, Pfeffer LM, Tuckey RC, Slominski AT, Noncalcemic 20-hydroxyvitamin D3 inhibits human melanoma growth in in vitro and in vivo models, Oncotarget, 8 (2017) 9823– 9834. 28039464 PMC5354773 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    20S(OH)D3 and 22(OH)D3 are detectable in human serum, epidermis and adrenal glands in vivo.

    “and are detectable in human serum, epidermis and adrenal glands in vivo [152]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EK, Tuckey RC, Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland, Sci Rep, 5 (2015) 14875. 26445902 PMC4597207

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All major dihydroxy- and trihydroxy-metabolites in Fig. 4 except 17α,20S(OH)2D3 have been detected in serum by LC/MS/MS but not quantified.

    “All the major dihydroxy- and trihydroxy-metabolites shown in Fig. 4 except 17α,20S(OH)2D3 (which has not been studied) have been detected in serum by LC/MS/MS, but not quantified (Table 3) [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, Tuckey RC, Novel activities of CYP11A1 and their potential physiological significance, The Journal of steroid biochemistry and molecular biology, 151 (2015) 25– 37. 25448732 PMC4757911 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP11A1 acts on vitamin D2 as well as D3, producing biologically active products.

    “CYP11A1 can act on vitamin D2 as well as D3, also producing biologically active products.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [180] Slominski AT, Kim TK, Janjetovic Z, Tuckey RC, Bieniek R, Yue J, Li W, Chen J, Nguyen MN, Tang EK, Miller D, Chen TC, Holick M, 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells, Am J Physiol Cell Physiol, 300 (2011) C526– 541. 21160030 PMC3063966 source

      Not checked in the free run.

    • cites [186] Nguyen MN, Slominski A, Li W, Ng YR, Tuckey RC, Metabolism of vitamin D2 to 17,20,24-trihydroxyvitamin D2 by cytochrome p450scc (CYP11A1), Drug metabolism and disposition: the biological fate of chemicals, 37 (2009) 761– 767. 19116262 PMC2659330 source

      Not checked in the free run.

    • cites [187] Slominski A, Semak I, Wortsman J, Zjawiony J, Li W, Zbytek B, Tuckey RC, An alternative pathway of vitamin D metabolism. Cytochrome P450scc (CYP11A1)-mediated conversion to 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2, The FEBS journal, 273 (2006) 2891– 2901. 16817851 PMC1893115 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1α,20S(OH)2D3 is not detectable in serum but is found in human epidermis, dermal fibroblasts, placenta and pig adrenal gland, indicating local production.

    “1α,20S(OH)2D3, while not being detectable in serum, was detected in human epidermis, dermal fibroblasts, placenta and pig adrenal gland, indicating local in vivo production [122, 152, 174].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [122] Slominski AT, Kim TK, Shehabi HZ, Semak I, Tang EK, Nguyen MN, Benson HA, Korik E, Janjetovic Z, Chen J, Yates CR, Postlethwaite A, Li W, Tuckey RC, In vivo evidence for a novel pathway of vitamin D(3) metabolism initiated by P450scc and modified by CYP27B1, FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 26 (2012) 3901– 3915. 22683847 PMC3425822 source

      Not checked in the free run.

    • cites [152] Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EK, Tuckey RC, Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland, Sci Rep, 5 (2015) 14875. 26445902 PMC4597207

      Not checked in the free run.

    • cites [174] Slominski AT, Kim TK, Li W, Tuckey RC, Classical and non-classical metabolic transformation of vitamin D in dermal fibroblasts, Exp Dermatol, 25 (2016) 231– 232. 26440881 PMC4789164

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Initial CYP11A1 hydroxylation of vitamin D2 is at C20, producing 20S(OH)D2 as the major product, with 17,20(OH)2D2 and 17,20,24(OH)3D2 as other products.

    “The initial hydroxylation is at C20 producing 20S(OH)D2 as the major product, with other products being 17,20(OH)2D2 and 17,20,24(OH)3D2 [180, 186, 187].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [180] Slominski AT, Kim TK, Janjetovic Z, Tuckey RC, Bieniek R, Yue J, Li W, Chen J, Nguyen MN, Tang EK, Miller D, Chen TC, Holick M, 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells, Am J Physiol Cell Physiol, 300 (2011) C526– 541. 21160030 PMC3063966 source

      Not checked in the free run.

    • cites [186] Nguyen MN, Slominski A, Li W, Ng YR, Tuckey RC, Metabolism of vitamin D2 to 17,20,24-trihydroxyvitamin D2 by cytochrome p450scc (CYP11A1), Drug metabolism and disposition: the biological fate of chemicals, 37 (2009) 761– 767. 19116262 PMC2659330 source

      Not checked in the free run.

    • cites [187] Slominski A, Semak I, Wortsman J, Zjawiony J, Li W, Zbytek B, Tuckey RC, An alternative pathway of vitamin D metabolism. Cytochrome P450scc (CYP11A1)-mediated conversion to 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2, The FEBS journal, 273 (2006) 2891– 2901. 16817851 PMC1893115 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    1α,20S,23S(OH)3D3 has been found in human serum, epidermis, placenta and pig adrenal gland.

    “To date 1α,20S,23S(OH)3D3 has been found in human serum (Table 3), epidermis, placenta and the pig adrenal gland.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These 20S(OH)D3 products are good substrates for CYP27B1 C1α hydroxylation, and their 1α-hydroxyderivatives are detected in skin.

    “In contrast to 20(OH)D3, they are all very good substrates for C1α hydroxylation by CYP27B1 [103] and their 1α-hydroxyderivatives have been detected in skin [152].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] Tang EK, Chen J, Janjetovic Z, Tieu EW, Slominski AT, Li W, Tuckey RC, Hydroxylation of CYP11A1-derived products of vitamin D3 metabolism by human and mouse CYP27B1, Drug metabolism and disposition: the biological fate of chemicals, 41 (2013) 1112– 1124. 23454830 PMC3629803 source

      Not checked in the free run.

    • cites [152] Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EK, Tuckey RC, Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland, Sci Rep, 5 (2015) 14875. 26445902 PMC4597207

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP27A1, CYP24A1, CYP2R1 and CYP3A4 can act on 20S(OH)D3 to produce 20,24(OH)2D3 and/or 20,25(OH)2D3 and/or 20,26(OH)2D3, all detected in serum.

    “CYP27A1, CYP24A1, CYP2R1 and CYP3A4 can act on 20S(OH)D3 producing 20,24(OH)2D3 and/or 20,25(OH)2D3 and/or 20,26(OH)2D3 and all these products have been detected in serum (Table 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Tang EK, Chen J, Janjetovic Z, Tieu EW, Slominski AT, Li W, Tuckey RC, Hydroxylation of CYP11A1-derived products of vitamin D3 metabolism by human and mouse CYP27B1, Drug metabolism and disposition: the biological fate of chemicals, 41 (2013) 1112– 1124. 23454830 PMC3629803 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These D2 secosteroids can act via VDR and RORα and γ.

    “They can act via the VDR [180] and RORα and γ [20, 21].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Slominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, Wang J, Postlethwaite A, Li W, Tuckey RC, Jetten AM, RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23dihydroxyvitamin D, FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 28 (2014) 2775– 2789. 24668754 PMC4062828

      Not checked in the free run.

    • cites [21] Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, Li W, Tuckey RC, Jetten AM, Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORalpha and RORgamma, The Journal of steroid biochemistry and molecular biology, 173 (2017) 42– 56. 27693422 PMC5373926 source

      Not checked in the free run.

    • cites [180] Slominski AT, Kim TK, Janjetovic Z, Tuckey RC, Bieniek R, Yue J, Li W, Chen J, Nguyen MN, Tang EK, Miller D, Chen TC, Holick M, 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells, Am J Physiol Cell Physiol, 300 (2011) C526– 541. 21160030 PMC3063966 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These D2 secosteroids are biologically active on normal and malignant skin cells, with anti-proliferative and pro-differentiation effects.

    “They also appear to be biologically active on normal and malignant skin cells displaying anti-proliferative and pro-differentiation effects [180, 187].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [180] Slominski AT, Kim TK, Janjetovic Z, Tuckey RC, Bieniek R, Yue J, Li W, Chen J, Nguyen MN, Tang EK, Miller D, Chen TC, Holick M, 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells, Am J Physiol Cell Physiol, 300 (2011) C526– 541. 21160030 PMC3063966 source

      Not checked in the free run.

    • cites [187] Slominski A, Semak I, Wortsman J, Zjawiony J, Li W, Zbytek B, Tuckey RC, An alternative pathway of vitamin D metabolism. Cytochrome P450scc (CYP11A1)-mediated conversion to 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2, The FEBS journal, 273 (2006) 2891– 2901. 16817851 PMC1893115 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These 5,7-dienes can be produced in tissues expressing CYP11A1, with some detectable in human epidermis, serum and pig adrenal glands.

    “These 5,7-dienes (including their precursors) can be produced in tissues expressing CYP11A1 [189, 190] with some of them being detectable in the human epidermis, serum and pig adrenal glands [152].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [152] Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EK, Tuckey RC, Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland, Sci Rep, 5 (2015) 14875. 26445902 PMC4597207

      Not checked in the free run.

    • cites [189] Slominski AT, Zmijewski MA, Semak I, Sweatman T, Janjetovic Z, Li W, Zjawiony JK, Tuckey RC, Sequential metabolism of 7-dehydrocholesterol to steroidal 5,7-dienes in adrenal glands and its biological implication in the skin, PLoS One, 4 (2009) e4309. 19190754 PMC2629546 source

      Not checked in the free run.

    • cites [190] Slominski AT, Kim TK, Chen J, Nguyen MN, Li W, Yates CR, Sweatman T, Janjetovic Z, Tuckey RC, Cytochrome P450scc-dependent metabolism of 7-dehydrocholesterol in placenta and epidermal keratinocytes, Int J Biochem Cell Biol, 44 (2012) 2003– 2018. 22877869 PMC3520099 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    These steroidal 5,7-dienes are predicted to undergo UVB phototransformation to secosteroids with short or no side chain that could enter the bloodstream.

    “It is predicted [188] that these steroidal 5,7-dienes will undergo phototransformation to the corresponding secosteroids after exposure to UVB in the skin, producing vitamin D derivatives with a short (pregnenolone-like) or no (androgenlike) side chain, which could potentially enter the bloodstream [59, 65, 191–193].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [188] Slominski A, Zjawiony J, Wortsman J, Semak I, Stewart J, Pisarchik A, Sweatman T, Marcos J, Dunbar C, C.T. R, A novel pathway for sequential transformation of 7dehydrocholesterol and expression of the P450scc system in mammalian skin, European journal of biochemistry, 271 (2004) 4178– 4188. 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [59] Slominski AT, Zmijewski MA, Semak I, Zbytek B, Pisarchik A, Li W, Zjawiony J, Tuckey RC, Cytochromes p450 and skin cancer: role of local endocrine pathways, Anticancer Agents Med Chem, 14 (2014) 77– 96. 23869782 PMC3740756

      Not checked in the free run.

    • cites [65] Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, Tuckey RC, Novel activities of CYP11A1 and their potential physiological significance, The Journal of steroid biochemistry and molecular biology, 151 (2015) 25– 37. 25448732 PMC4757911 source

      Not checked in the free run.

    • cites [191] Zmijewski MA, Li W, Chen J, Kim TK, Zjawiony JK, Sweatman TW, Miller DD, Slominski AT, Synthesis and photochemical transformation of 3beta,21-dihydroxypregna-5,7-dien20-one to novel secosteroids that show anti-melanoma activity, Steroids, 76 (2011) 193– 203. 21070794 PMC3005096 source

      Not checked in the free run.

    • cites [192] Zmijewski MA, Li W, Zjawiony JK, Sweatman TW, Chen J, Miller DD, Slominski AT, Photo-conversion of two epimers (20R and 20S) of pregna-5,7-diene-3beta, 17alpha, 20-triol and their bioactivity in melanoma cells, Steroids, 74 (2009) 218– 228. 19028513 PMC2631623 source

      Not checked in the free run.

    • cites [193] Slominski AT, Brozyna AA, Skobowiat C, Zmijewski MA, Kim TK, Janjetovic Z, Oak AS, Jozwicki W, Jetten AM, Mason RS, Elmets C, Li W, Hoffman RM, Tuckey RC, On the role of classical and novel forms of vitamin D in melanoma progression and management, J Steroid Biochem Mol Biol, (2017). PMC5748362 28676457

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These Δ7-steroids and their secosteroidal derivatives have biological activities in normal and malignant cells without apparently influencing calcium metabolism.

    “These Δ7-steroids and their secosteroidal derivatives display biological activities in normal and malignant cells [194], apparently without influencing calcium metabolism [195].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [194] Slominski A, Kim TK, Zmijewski MA, Janjetovic Z, Li W, Chen J, Kusniatsova EI, Semak I, Postlethwaite A, Miller DD, Zjawiony JK, Tuckey RC, Novel vitamin D photoproducts and their precursors in the skin, Dermatoendocrinol, 5 (2013) 7– 19. 24494038 PMC3897599 source

      Not checked in the free run.

    • cites [195] Holick MF, Garabedian M, Schnoes HK, DeLuca HF, Relationship of 25-hydroxyvitamin D3 side chain structure to biological activity, J Biol Chem, 250 (1975) 226– 230. 1141205

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    They show in vitro anti-proliferative effects against melanoma cells, melanocytes, keratinocytes and fibroblasts and anti-fibrotic activities.

    “they show in vitro anti-proliferative effects against melanoma cells, melanocytes, keratinocytes and fibroblasts as well as anti-fibrotic activities [189, 191, 192, 194, 196, 197]”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [189] Slominski AT, Zmijewski MA, Semak I, Sweatman T, Janjetovic Z, Li W, Zjawiony JK, Tuckey RC, Sequential metabolism of 7-dehydrocholesterol to steroidal 5,7-dienes in adrenal glands and its biological implication in the skin, PLoS One, 4 (2009) e4309. 19190754 PMC2629546 source

      Not checked in the free run.

    • cites [191] Zmijewski MA, Li W, Chen J, Kim TK, Zjawiony JK, Sweatman TW, Miller DD, Slominski AT, Synthesis and photochemical transformation of 3beta,21-dihydroxypregna-5,7-dien20-one to novel secosteroids that show anti-melanoma activity, Steroids, 76 (2011) 193– 203. 21070794 PMC3005096 source

      Not checked in the free run.

    • cites [192] Zmijewski MA, Li W, Zjawiony JK, Sweatman TW, Chen J, Miller DD, Slominski AT, Photo-conversion of two epimers (20R and 20S) of pregna-5,7-diene-3beta, 17alpha, 20-triol and their bioactivity in melanoma cells, Steroids, 74 (2009) 218– 228. 19028513 PMC2631623 source

      Not checked in the free run.

    • cites [194] Slominski A, Kim TK, Zmijewski MA, Janjetovic Z, Li W, Chen J, Kusniatsova EI, Semak I, Postlethwaite A, Miller DD, Zjawiony JK, Tuckey RC, Novel vitamin D photoproducts and their precursors in the skin, Dermatoendocrinol, 5 (2013) 7– 19. 24494038 PMC3897599 source

      Not checked in the free run.

    • cites [196] Slominski AT, Li W, Bhattacharya SK, Smith RA, Johnson PL, Chen J, Nelson KE, Tuckey RC, Miller D, Jiao Y, Gu W, Postlethwaite AE, Vitamin D analogs 17,20S(OH)2pD and 17,20R(OH)2pD are noncalcemic and exhibit antifibrotic activity, J Invest Dermatol, 131 (2011) 1167– 1169. 21228816 PMC3078214 source

      Not checked in the free run.

    • cites [197] Wasiewicz T, Szyszka P, Cichorek M, Janjetovic Z, Tuckey RC, Slominski AT, Zmijewski MA, Antitumor effects of vitamin D analogs on hamster and mouse melanoma cell lines in relation to melanin pigmentation, Int J Mol Sci, 16 (2015) 6645– 6667. 25811927 PMC4424981

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    21(OH)pD increases keratinocyte sensitivity to reactive oxygen species and stimulates expression of hypothalamus-pituitary-adrenal axis elements in keratinocytes.

    “21(OH)pD (pregnacalciferol) also increased the sensitivity of keratinocytes to reactive oxygen species (ROS) [198] and stimulated the expression of elements of the hypothalamus-pituitary-adrenal axis in keratinocytes [199].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [198] Piotrowska A, Wierzbicka J, Slebioda T, Wozniak M, Tuckey RC, Slominski AT, Zmijewski MA, Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes, Steroids, 110 (2016) 49– 61. 27083311 PMC4853285 source

      Not checked in the free run.

    • cites [199] Wierzbicka JM, Zmijewski MA, Piotrowska A, Nedoszytko B, Lange M, Tuckey RC, Slominski AT, Bioactive forms of vitamin D selectively stimulate the skin analog of the hypothalamus-pituitary-adrenal axis in human epidermal keratinocytes, Mol Cell Endocrinol, 437 (2016) 312– 322. 27524410 PMC5048597

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    25,26,27-trinor-23-ene-1α-hydroxyvitamin D3 is a minor CYP24A1 product from 1α,25(OH)2D3, likely from cleavage between C24 and C25.

    “Another secosteroid, 25,26,27-trinor-23-ene-1α-hydroxyvitamin D3 has been identified as a minor product of CYP24A1 action on 1α,25(OH)2D3 [203], presumably arising from some cleavage between C24 and C25 rather than C23 and C24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Hamamoto H, Kusudo T, Urushino N, Masuno H, Yamamoto K, Yamada S, Kamakura M, Ohta M, Inouye K, Sakaki T, Structure-function analysis of vitamin D 24-hydroxylase (CYP24A1) by site-directed mutagenesis: amino acid residues responsible for species-based difference of CYP24A1 between humans and rats, Molecular pharmacology, 70 (2006) 120– 128. 16617161

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human CYP24A1 releases intermediates from its active site, as confirmed by serum 24R,25(OH)2D3, and these intermediates compete with substrate for conversion to calcitroic acid.

    “Kinetic studies on human CYP24A1 show that the enzyme releases the intermediates from the active site (as confirmed by the presence of 24R,25(OH)2D3 in the serum) and they must compete with substrate and other intermediates for conversion to calcitroic acid [113].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Tieu EW, Tang EK, Tuckey RC, Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway, The FEBS journal, 281 (2014) 3280– 3296. 24893882

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These C23 intermediates are hydroxylated at C26, forming a C23-C26 lactol that is oxidized to lactone, 1α,25(OH)2D3-23-26-lactone for 1α,25(OH)2D3.

    “These are subsequently hydroxylated at C26 followed by formation of the C23-C26 lactol which is oxidized to the lactone, 1α,25(OH)2D3–23-26-lactone in the case of 1α,25(OH)2D3 (Fig. 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Sakaki T, Sawada N, Komai K, Shiozawa S, Yamada S, Yamamoto K, Ohyama Y, Inouye K, Dual metabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24, European journal of biochemistry, 267 (2000) 6158– 6165. 11012668

      Not checked in the free run.

    • cites [113] Tieu EW, Tang EK, Tuckey RC, Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway, The FEBS journal, 281 (2014) 3280– 3296. 24893882

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activity of 1α,25(OH)2D3 metabolites on intestinal calcium absorption and bone calcium mobilization in chick declines with successive C24 oxidation steps, with 24-oxo-1α,23S,25-(OH)3D3 having only a modest effect.

    “The activity of 1α,25(OH)2D3 metabolites on intestinal calcium absorption and bone calcium mobilization in the chick declined with successive steps in the C24 oxidation pathway with the third product, 24-oxo-1α,23S,25-(OH)3D3, having only a modest effect [204].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Mayer E, Bishop JE, Ohnuma N, Norman AW, Biological activity assessment of the vitamin D metabolites 1,25-dihydroxy-24-oxo-vitamin D3 and 1,23,25-trihydroxy-24-oxovitamin D3, Archives of biochemistry and biophysics, 224 (1983) 671– 676. 6307158

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both C24 and C23 CYP24A1 pathways are believed primarily to inactivate 1α,25(OH)2D3 and remove 25(OH)D3, but some metabolites retain activity.

    “While both the C24 and C23 oxidation pathways catalyzed by CYP24A1 are believed to be primarily involved in inactivation of 1α,25(OH)2D3 and removal of its precursor 25(OH)D3, some metabolites retain activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    24-oxo-1α,23S,25(OH)3D3 is equipotent to 1α,25(OH)2D3 in suppressing PTH secretion by bovine parathyroid cells, despite being 10 times less effective at VDR binding.

    “It was also equipotent in the suppression of parathyroid hormone secretion by bovine parathyroid cells, despite being 10 times less effective than 1α,25(OH)2D3 in competing with radiolabeled 1α,25(OH)2D3 for binding to the VDR [206].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Lee NE, Reddy GS, Brown AJ, Williard PG, Synthesis, stereochemistry, and biological activity of 1alpha,23,25-trihydroxy-24-oxovitamin D3, a major natural metabolite of 1alpha,25dihydroxyvitamin D3, Biochemistry, 36 (1997) 9429– 9437. 9235987

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    All these C23 intermediates are likely present at low levels in human serum, with 1α,25(OH)2D3-23-26-lactone detected in rats and dogs given 1α,25(OH)2D3.

    “All these intermediates are also likely to be present at low levels in human serum, with 1α,25(OH)2D3–23-26-lactone having been detected in the serum of rats and dogs administered 1α,25(OH)2D3 [201, 202].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [201] Ishizuka S, Ishimoto S, Norman AW, Isolation and identification of 1 alpha,25-dihydroxy24-oxovitamin D3, 1 alpha,25-dihydroxyvitamin D3 26,23-lactone, and 1 alpha,24(S),25trihydroxyvitamin D3: in vivo metabolites of 1 alpha,25-dihydroxyvitamin D3, Biochemistry, 23 (1984) 1473– 1478. 6547052

      Not checked in the free run.

    • cites [202] Sekimoto H, Siu-Caldera ML, Weiskopf A, Vouros P, Muralidharan KR, Okamura WH, Uskokovic MR, Reddy GS, 1alpha,25-dihydroxy-3-epi-vitamin D3: in vivo metabolite of 1alpha,25-dihydroxyvitamin D3 in rats, FEBS letters, 448 (1999) 278– 282. 10218492

      Not checked in the free run.

    • Rests on an assumption: Enzyme activities observed in vitro or in animal models predict the presence and metabolism of the same vitamin D metabolites in human serum.

  • May combine two claims.

    Premisecitation

    1α,24S,25,28(OH)4D2 has low biological activity in rats compared to 1α,25(OH)2D3 for intestinal calcium transport and bone resorption, consistent with CYP24A1 inactivation of 1α,25(OH)2D2.

    “The biological activity of 1α,24S,25,28(OH)4D2 was tested in rats and found to be low compared to 1α,25(OH)2D3 with respect to intestinal calcium transport and bone calcium resorption [210], so conversion to this product is consistent with an inactivation role for CYP24A1 on 1α,25(OH)2D2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [210] Rao DS, Siu-Caldera ML, Uskokovic MR, Horst RL, Reddy GS, Physiological significance of C-28 hydroxylation in the metabolism of 1alpha,25-dihydroxyvitamin D(2), Archives of biochemistry and biophysics, 368 (1999) 319– 328. 10441383

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP27A1 produces 25(OH)D3 as the major product from vitamin D3, with minor tentatively identified (25R)-27(OH)D3 and (25S)-27(OH)D3.

    “CYP27A1 acts on vitamin D3 producing 25(OH)D3 as the major product but other minor metabolites including (25R)-27(OH)D3 and (25S)-27(OH)D3 have been tentatively identified in studies with the enzyme expressed in COS-1 monkey kidney cells [87] and E. coli [123].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Guo YD, Strugnell S, Back DW, Jones G, Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions, Proceedings of the National Academy of Sciences of the United States of America, 90 (1993) 8668– 8672. 7690968 PMC47419

      Not checked in the free run.

    • cites [123] Sawada N, Sakaki T, Ohta M, Inouye K, Metabolism of vitamin D(3) by human CYP27A1, Biochemical and biophysical research communications, 273 (2000) 977– 984. 10891358

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some 24-oxo-25,26,27-trinor-1α(OH)D2 is produced, indicating C24-C25 bond cleavage from 1α,24,25(OH)3D2.

    “Some 24-oxo-25,26,27-trinor-1α(OH)D2 was also produced indicating bond cleavage can occur between C24 and C25, from precursor 1α,24,25(OH)3D2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Urushino N, Yasuda K, Ikushiro S, Kamakura M, Ohta M, Sakaki T, Metabolism of 1alpha,25-dihydroxyvitamin D2 by human CYP24A1, Biochemical and biophysical research communications, 384 (2009) 144– 148. 19393625

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    25(OH)D2 is metabolized to 24R,25,28(OH)3D2 and 24S,25,28(OH)3D2 by perfused rat kidneys and rat kidney homogenates, with further metabolism to water-soluble products.

    “It has also been shown to be metabolized to 24R,25,28(OH)3D2 and 24S,25,28(OH)3D2 by perfused rat kidneys and rat kidney homogenates with evidence for further metabolism to water-soluble products [214], presumably by CYP24A1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Rao LS, Ray R, Holick MF, Horst RL, Uskokovic MR, Reddy GS, Metabolism of [3alpha-3H] 25-hydroxyvitamin D2 in kidneys isolated from normal and vitamin D2-intoxicated rats, J Nutr Sci Vitaminol (Tokyo), 46 (2000) 222– 229. 11234914

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    For 20S(OH)D3, CYP24A1 may activate by C24 or C25 hydroxylation, giving products more potent than 20S(OH)D3 and 1α,25(OH)2D3 for inhibiting melanoma colony formation.

    “For 20S(OH)D3, CYP24A1 may play an activating role since hydroxylation at C24 or C25 by this enzyme gives products more potent than 20S(OH)D3 (and 1α,25(OH)2D3) for the inhibition of colony formation by melanoma cells [208].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] Tieu EW, Tang EK, Chen J, Li W, Nguyen MN, Janjetovic Z, Slominski A, Tuckey RC, Rat CYP24A1 acts on 20-hydroxyvitamin D(3) producing hydroxylated products with increased biological activity, Biochem Pharmacol, 84 (2012) 1696– 1704. 23041230 PMC3501553 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1α,25(OH)2D2 is metabolized to 1α,24,25(OH)3D2 by bovine kidney homogenates, likely CYP24A1, and this metabolite poorly stimulates intestinal calcium transport and bone resorption in rats.

    “Metabolism of 1α,25(OH)2D2 to 1α,24,25(OH)3D2 by bovine kidney homogenates, presumably by CYP24A1, was reported in 1986, with this metabolite showing poor ability to stimulate intestinal calcium transport and bone resorption in rats compared to 1α,25(OH)2D3 [209].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Horst RL, Reinhardt TA, Ramberg CF, Koszewski NJ, Napoli JL, 24-Hydroxylation of 1,25-dihydroxyergocalciferol. An unambiguous deactivation process, The Journal of biological chemistry, 261 (1986) 9250– 9256. 3013880

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human HepG2 cells can hydroxylate 1α-(OH)D2 at C24 to produce 1α,24S(OH)2D2, suggesting the 24S isomer may form from vitamin D2.

    “Human HepG2 cells (which express CYP27A1) can hydroxylate 1α-(OH)D2 at C24 producing 1α,24S(OH)2D2 suggesting that the 24S isomer might also be produced with vitamin D2 as substrate [87].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Guo YD, Strugnell S, Back DW, Jones G, Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions, Proceedings of the National Academy of Sciences of the United States of America, 90 (1993) 8668– 8672. 7690968 PMC47419

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1α,24(OH)2D2 binds VDR and inhibits skin cell proliferation with potency comparable to 1α,25(OH)2D3, but has lesser ability to raise serum calcium in rats.

    “1α,24(OH)2D2 is biologically active, binding to the VDR and inhibiting skin cell proliferation with comparable potency to 1α,25(OH)2D3, but with a lesser ability to raise serum calcium levels in rats [216, 218, 219].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [216] Horst RL, Koszewski NJ, Reinhardt TA, 1 alpha-hydroxylation of 24-hydroxyvitamin D2 represents a minor physiological pathway for the activation of vitamin D2 in mammals, Biochemistry, 29 (1990) 578– 582. 2154251

      Not checked in the free run.

    • cites [218] Jones G, Byford V, Makin HL, Kremer R, Rice RH, deGraffenried LA, Knutson JC, Bishop CW, Anti-proliferative activity and target cell catabolism of the vitamin D analog 1 alpha,24(S)-(OH)2D2 in normal and immortalized human epidermal cells, Biochem Pharmacol, 52 (1996) 133– 140. 8678897

      Not checked in the free run.

    • cites [219] Knutson JC, LeVan LW, Valliere CR, Bishop CW, Pharmacokinetics and systemic effect on calcium homeostasis of 1 alpha,24-dihydroxyvitamin D2 in rats. Comparison with 1 alpha,25dihydroxyvitamin D2, calcitriol, and calcipotriol, Biochem Pharmacol, 53 (1997) 829– 837. 9113104

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both C25 epimers of 27(OH)D3 stimulate intestinal calcium binding protein production and increase serum calcium in vitamin D-deficient rats on a low-calcium diet.

    “Both C25 epimers of 27(OH)D3 were reported to stimulate the production of intestinal calcium binding protein and to increase serum calcium levels in vitamin D-deficient rats fed a low-calcium diet [215].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [215] Thomasset M, Redel J, Intestinal calcium-binding protein and bone calcium mobilization in response to (25R)- and (25S)-26-hydroxycholecalciferol in rats, Journal of steroid biochemistry, 13 (1980) 803– 807. 7412291

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    24(OH)D2 concentrations were in the nM range while 1α,24(OH)2D2 levels were in the pM range and comparable to 1α,25(OH)2D2 concentrations.

    “24(OH)D2 concentrations were in the nM range while 1α,24(OH)2D2 levels were in the pM range and generally comparable to the 1α,25(OH)2D2 concentrations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Mawer EB, Jones G, Davies M, Still PE, Byford V, Schroeder NJ, Makin HL, Bishop CW, Knutson JC, Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum, The Journal of clinical endocrinology and metabolism, 83 (1998) 2156– 2166. 9626155

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    24(OH)D2 and its CYP27B1 metabolite 1α,24(OH)2D2 are detected in serum of patients treated with large daily vitamin D2 doses.

    “This product and its CYP27B1 metabolite, 1α,24(OH)2D2, have been detected in the serum of patients treated with a large daily dose of vitamin D2 [217].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Mawer EB, Jones G, Davies M, Still PE, Byford V, Schroeder NJ, Makin HL, Bishop CW, Knutson JC, Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum, The Journal of clinical endocrinology and metabolism, 83 (1998) 2156– 2166. 9626155

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    3-epi-1α,25(OH)2D2 is detected in rat plasma after pharmacological 1α,25(OH)2D2, indicating the reaction occurs in vivo.

    “3-epi-1α,25(OH)2D2 has been detected in rat plasma following the administration of a pharmacological dose of 1α,25(OH)2D2, indicating the reaction occurs in vivo [202].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Sekimoto H, Siu-Caldera ML, Weiskopf A, Vouros P, Muralidharan KR, Okamura WH, Uskokovic MR, Reddy GS, 1alpha,25-dihydroxy-3-epi-vitamin D3: in vivo metabolite of 1alpha,25-dihydroxyvitamin D3 in rats, FEBS letters, 448 (1999) 278– 282. 10218492

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    25-hydroxyvitamin D 3-epimerase converts 25(OH)D3 to 3-epi-25(OH)D3 and 25(OH)D2 to 3-epi-25(OH)D2, and both epimers are present in human serum.

    “25-hydroxyvitamin D 3-epimerase converts 25(OH)D3 to 3-epi-25(OH)D3 and 25(OH)D2 to 3-epi-25(OH)D2, and both of these epimers are present in human serum.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    L3 and some CYP11A1-derived products are present in serum.

    “We observed that L3 and some of its CYP11A1-derived products are present in serum (Table 1) [225].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Slominski AT, Kim TK, Hobrath JV, Janjetovic Z, Oak ASW, Postlethwaite A, Lin Z, Li W, Takeda Y, Jetten AM, Tuckey RC, Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols, Sci Rep, 7 (2017) 11434. 28900196 PMC5595834 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP3A4 hydroxylates 25(OH)D3 to 23R,25(OH)2D3, 4β,25(OH)2D3, 4α,25(OH)2D3 and 25,26(OH)2D3, which have been measured in serum.

    “CYP3A4 hydroxylates 25(OH)D3 producing 23R,25(OH)2D3, 4β,25(OH)2D3, 4α,25(OH)2D3 and 25,26(OH)2D3 [153], which have been measured in serum (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Wang Z, Lin YS, Zheng XE, Senn T, Hashizume T, Scian M, Dickmann LJ, Nelson SD, Baillie TA, Hebert MF, Blough D, Davis CL, Thummel KE, An inducible cytochrome P450 3A4dependent vitamin D catabolic pathway, Molecular pharmacology, 81 (2012) 498– 509. 22205755 PMC3310418

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP3A4 acts as an alternative 25-hydroxylase to CYP2R1 on vitamin D2, producing 25(OH)D2, but cannot 25-hydroxylate vitamin D3.

    “CYP3A4 acts as an alternative 25-hydroxylase to CYP2R1 on vitamin D2 producing 25(OH)D2, but unlike CYP2R1 it cannot hydroxylate vitamin D3 at C25 [223, 224].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [223] Gupta RP, He YA, Patrick KS, Halpert JR, Bell NH, CYP3A4 is a vitamin D-24- and 25hydroxylase: analysis of structure function by site-directed mutagenesis, The Journal of clinical endocrinology and metabolism, 90 (2005) 1210– 1219. 15546903

      Not checked in the free run.

    • cites [224] Gupta RP, Hollis BW, Patel SB, Patrick KS, Bell NH, CYP3A4 is a human microsomal vitamin D 25-hydroxylase, Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research, 19 (2004) 680– 688. 15005856

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tachysterol3 absorbs UV and converts to L3 via previtamin D3, so L3 predominates in skin after extended UVB.

    “Tachysterol3 also absorbs UV radiation which converts it to L3 via previtamin D3 so that L3 predominates in skin after extended exposure to UVB [2, 3].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Wacker M, Holick MF, Sunlight and Vitamin D: A global perspective for health, Dermatoendocrinol, 5 (2013) 51– 108. 24494042 PMC3897598 source

      Not checked in the free run.

    • cites [3] Holick MF, Vitamin D: A millenium perspective, Journal of cellular biochemistry, 88 (2003) 296– 307. 12520530 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chemically synthesized 1α,25(OH)2L3 is an excellent agonist for the VDR non-genomic pocket and has photoprotective effects via increased DNA repair enzyme expression.

    “Chemically synthesized 1α,25(OH)2L3, while not identified as a natural product, is an excellent agonist for the non-genomic pocket of the VDR (A-pocket) and has photoprotective effects mediated by increased expression of DNA repair enzymes [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Dixon KM, Norman AW, Sequeira VB, Mohan R, Rybchyn MS, Reeve VE, Halliday GM, Mason RS, 1alpha,25(OH)(2)-vitamin D and a nongenomic vitamin D analogue inhibit ultraviolet radiation-induced skin carcinogenesis, Cancer Prev Res (Phila), 4 (2011) 1485– 1494. 21733837

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All these hydroxylumisterols are also detected in skin, which has low CYP11A1.

    “All these hydroxylumisterols were also detected in skin [225] which contains a low CYP11A1 concentration [115, 188].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [225] Slominski AT, Kim TK, Hobrath JV, Janjetovic Z, Oak ASW, Postlethwaite A, Lin Z, Li W, Takeda Y, Jetten AM, Tuckey RC, Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols, Sci Rep, 7 (2017) 11434. 28900196 PMC5595834 source

      Not checked in the free run.

    • cites [115] Slominski A, Zbytek B, Nikolakis G, Manna PR, Skobowiat C, Zmijewski M, Li W, Janjetovic Z, Postlethwaite A, Zouboulis CC, Tuckey RC, Steroidogenesis in the skin: implications for local immune functions, The Journal of steroid biochemistry and molecular biology, 137 (2013) 107– 123. 23435015 PMC3674137 source

      Not checked in the free run.

    • cites [188] Slominski A, Zjawiony J, Wortsman J, Semak I, Stewart J, Pisarchik A, Sweatman T, Marcos J, Dunbar C, C.T. R, A novel pathway for sequential transformation of 7dehydrocholesterol and expression of the P450scc system in mammalian skin, European journal of biochemistry, 271 (2004) 4178– 4188. 15511223 PMC1201497 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vitamin D status is routinely assessed by serum 25(OH)D3 because it is relatively easy to measure and has a half-life of 2-3 weeks.

    “Vitamin D status is routinely assessed by measuring serum 25(OH)D3 levels as this is relatively easy to measure and has a long half-life in the bloodstream, in the order of 2–3 weeks [129].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab, 96 (2011) 1911– 1930. 21646368

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    1α,25(OH)2D3 has a half-life of about 4 h and does not necessarily reflect long-term vitamin D status.

    “Also, it has a much shorter half-life, in the order of 4 h, and thus does not necessarily reflect long term vitamin D status.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Tachysterol3 metabolism is not well studied, but based on L3 data it is likely present in serum and possibly metabolized by CYP11A1 or other vitamin D-metabolizing CYPs.

    “Metabolism of the other previtamin D3 over-radiation product, tachysterol3, has not been investigated in detail yet but based on the L3 data it is likely to be present in the serum and possibly metabolized by CYP11A1 or other vitamin D-metabolizing CYPs.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Enzyme activities observed in vitro or in animal models predict the presence and metabolism of the same vitamin D metabolites in human serum.

  • May combine two claims.

    Interpretationcitation

    Docking studies predict CYP11A1-derived hydroxylumisterols bind the non-genomic VDR site better than the genomic site, suggesting this binding may mediate activity.

    “Docking studies predict that the CYP11A1-derived hydroxylumisterols also bind to this site better than to the genomic site suggesting that this binding may mediate their activity [225].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [225] Slominski AT, Kim TK, Hobrath JV, Janjetovic Z, Oak ASW, Postlethwaite A, Lin Z, Li W, Takeda Y, Jetten AM, Tuckey RC, Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols, Sci Rep, 7 (2017) 11434. 28900196 PMC5595834 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    1α,25(OH)2D3 is more difficult to measure, present at almost 1000-fold lower concentration than 25(OH)D3.

    “1α,25(OH)2D3 on the other hand is more difficult to measure, being present in serum at a concentration almost 1000 fold lower than that of 25(OH)D3.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisecitation

    3-Epi-25(OH)D3 is now routinely measured separately from 25(OH)D3 and is generally regarded as a less active precursor.

    “3-Epi-25(OH)D3 is now routinely measured separately from 25(OH)D3 as it is generally regarded as a “less active precursor” as described in Section 2.1.3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    20S(OH)D3, 22(OH)D3, and 20,23(OH)2D3 are produced when CYP11A1 acts on vitamin D3.

    “which result from the action of CYP11A1 on vitamin D3 (section 2.2.6)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Chemical synthesis of deuterated or 13C-labelled secosteroids can be a major undertaking or expense.

    “their chemical synthesis can represent a major endeavor or expense.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The rationale for VMR is that 24R,25(OH)2D3 concentration reflects 1α,25(OH)2D3 activity on VDR because 1α,25(OH)2D3 strongly stimulates CYP24A1 expression, which converts 25(OH)D3 to 24R,25(OH)2D3.

    “The rationale for its use is that the 24R,25(OH)2D3 concentration provides information on the activity of 1α,25(OH)2D3 on the VDR since 1α,25(OH)2D3 strongly stimulates the expression of CYP24A1, which encodes the enzyme responsible for converting 25(OH)D3 into 24R,25(OH)2D3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Measuring 24R,25(OH)2D with 25(OH)D3 provides additional information on vitamin D status and defines the vitamin D metabolite ratio (VMR).

    “The measurement of 24R,25(OH)2D levels along with that of 25(OH)D3 has been reported to provide additional useful information on vitamin D status and has led to the determination of the serum 24R,25(OH)2D3 to 25(OH)D3 ratio, referred to as the vitamin D metabolite ratio (VMR) [139, 149, 151, 226, 227].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [139] Baecher S, Leinenbach A, Wright JA, Pongratz S, Kobold U, Thiele R, Simultaneous quantification of four vitamin D metabolites in human serum using high performance liquid chromatography tandem mass spectrometry for vitamin D profiling, Clinical biochemistry, 45 (2012) 1491– 1496. 22771503

      Not checked in the free run.

    • cites [149] Berg AH, Powe CE, Evans MK, Wenger J, Ortiz G, Zonderman AB, Suntharalingam P, Lucchesi K, Powe NR, Karumanchi SA, Thadhani RI, 24,25-Dihydroxyvitamin d3 and vitamin D status of community-dwelling black and white Americans, Clin Chem, 61 (2015) 877– 884. 25922442 PMC4686255

      Not checked in the free run.

    • cites [151] Wagner D, Hanwell HE, Schnabl K, Yazdanpanah M, Kimball S, Fu L, Sidhom G, Rousseau D, Cole DE, Vieth R, The ratio of serum 24,25-dihydroxyvitamin D(3) to 25hydroxyvitamin D(3) is predictive of 25-hydroxyvitamin D(3) response to vitamin D(3) supplementation, The Journal of steroid biochemistry and molecular biology, 126 (2011) 72– 77. 21605672

      Not checked in the free run.

    • cites [226] Ginsberg C, Katz R, de Boer IH, Kestenbaum BR, Chonchol M, Shlipak MG, Sarnak MJ, Hoofnagle AN, Rifkin DE, Garimella PS, Ix JH, The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study, Bone, 107 (2017) 124– 130. 29155243 PMC5794222

      Not checked in the free run.

    • cites [227] Cashman KD, Hayes A, Galvin K, Merkel J, Jones G, Kaufmann M, Hoofnagle AN, Carter GD, Durazo-Arvizu RA, Sempos CT, Significance of serum 24,25-dihydroxyvitamin D in the assessment of vitamin D status: a double-edged sword?, Clin Chem, 61 (2015) 636– 645. 25710460

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    L3 and its side-chain hydroxyderivatives show potent biological activity on cultured cells, with some effects resembling those of 1α,25(OH)2D3.

    “they display potent biological activity on cultured cells, with some effects similar to those displayed by 1α,25(OH)2D3.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Unlike 3-epi-25(OH)D3, 25(OH)D3-3-sulfate may have physiological activity because it can be converted to 1α,25(OH)2D3.

    “but unlike 3-epi-25(OH)D3 it may be physiologically active in terms of being able to be converted to 1α,25(OH)2D3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Mass spectrometry does not distinguish well between different monohydroxyvitamin D3 species or between different dihydroxyvitamin D3 species, because many geometric and stereoisomers give similar ions.

    “Since mass spectrometry is not particularly good at distinguishing between different monohydroxyvitamin D3 species or between different dihydroxyvitamin D3 species, with many geometric and stereoisomers displaying similar ions”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Deuterated or 13C-labelled secosteroids are needed as standards for mass-spectrometric quantitation.

    “Deuterated or 13C-labelled secosteroids are required as standards for quantitation by mass spectrometry”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    20S(OH)D3 inhibits cell proliferation and promotes keratinocyte differentiation with potency similar to 1α,25(OH)2D3, but it does not affect calcium levels and has only a minimal effect on CYP24A1 expression.

    “20S(OH)D3 inhibits cell proliferation and promotes keratinocyte differentiation with a potency similar to 1α,25(OH)2D3, but has no effect on calcium levels and only a minimal effect on CYP24A1 expression [66, 67].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] Slominski AT, Manna PR, Tuckey RC, On the role of skin in the regulation of local and systemic steroidogenic activities, Steroids, 103 (2015) 72– 88. 25988614 PMC4631694

      Not checked in the free run.

    • cites [67] Slominski AT, Kim TK, Li W, Yi AK, Postlethwaite A, Tuckey RC, The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions, The Journal of steroid biochemistry and molecular biology, 144PA (2014) 28– 39. PMC4002668 24176765 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In elderly adults, the vitamin D metabolite ratio (VMR) and higher serum 24R,25(OH)2D3, but not serum 25(OH)D3, were associated with a lower incidence of hip fractures.

    “Both the VMR and higher 24R,25(OH)2D3, but not the 25(OH)D3 concentration, were found to correlate with a decreased incidence of hip fractures in elderly adults [226].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] Ginsberg C, Katz R, de Boer IH, Kestenbaum BR, Chonchol M, Shlipak MG, Sarnak MJ, Hoofnagle AN, Rifkin DE, Garimella PS, Ix JH, The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study, Bone, 107 (2017) 124– 130. 29155243 PMC5794222

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    UV radiation, but not dietary vitamin D3 or D2 supplements, will raise levels of L3 and its side-chain hydroxyderivatives.

    “UV radiation but not dietary supplements of these vitamins, will elevate their levels.”
    Quote in the paperSubstantial claim
128 of 128

  • The paper relies on this without support.

    Enzyme activities observed in vitro or in animal models predict the presence and metabolism of the same vitamin D metabolites in human serum.

    “Thus we predict that all intermediates, except the unstable aldehyde (1α-(OH)-23-oxo-24,25,26,27-tetranorvitamin D3), will be present in human serum.”

  • The paper relies on this without support.

    The absence of published reports about a metabolite in serum indicates that the metabolite has not been found in serum.

    “To our knowledge there are no reports of 24R,25(OH)2D2, a product of CYP24A1 action on 25(OH)D2, being present in the serum”

  • The paper relies on this without support.

    Potency observed in in vitro experiments is predictive of physiological importance in vivo.

    “In vitro experiments indicate high potency, in many cases comparable to 1α,25(OH)2D3, so serum concentrations in the low nM range may be enough for an important physiological role.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Slominski, 2017, On the role of classical and novel forms of vitamin D in melanoma progression and management, J. Steroid Biochem. Mol. Biol.
  2. Sakaki, 2005, Metabolism of vitamin D3 by cytochromes P450, Front Biosci, 10, 119

Cited by

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Related

Authors
Tuckey, R. C., Cheng, C. Y. S., & Slominski, A. T.
Affiliations
  • The University of Western Australia (AU)
  • University of Alabama at Birmingham (US)
Corresponding author
Tuckey, Robert C.
ORCID
Venue
The Journal of Steroid Biochemistry and Molecular Biology
Publisher
Elsevier BV
Published
2019-02
Volume
186
Pages
4-21
ISSN
0960-0760 (ISSN-L)
DOI
10.1016/j.jsbmb.2018.09.003
PMC
PMC6342654
OpenAlex
W2891847712
Semantic Scholar
83cd8404c2a91cbcd47977c4367bbe7d70510d28
Cited by
245
References
231
Citations by year
2026: 20 · 2025: 28 · 2024: 41 · 2023: 44 · 2022: 40 · 2021: 39 · 2020: 24 · 2019: 9
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
Funders
  • University of Western Australia and the Research Training Program
  • NIH (1R01AR056666-01A2, R21AR066505, 1R01AR071189–01A1, R01AR073004)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
Keywords
vitamin D status, 25-hydroxyvitamin D, 1α,25-dihydroxyvitamin D, CYP24A1, CYP11A1, 24R,25-dihydroxyvitamin D3, 3-epi-25-hydroxyvitamin D3, vitamin D hydroxylation, vitamin D3, vitamin D2
MeSH terms
Animals, Cholesterol Side-Chain Cleavage Enzyme, Chromatography, Liquid, Humans, Vitamin D, Vitamins, Tandem Mass Spectrometry, Metabolomics, Metabolome, Vitamin D3 24-Hydroxylase

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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