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Cited by 294Steroid Chemistry and BiochemistryCholesterol and Lipid MetabolismAdrenal Hormones and Disorders

Novel activities of CYP11A1 and their potential physiological significance

Open access
Slominski, Andrzej T., Li, Wei, Kim, Tae-Kang, Semak, Igor, Wang, Jin, Zjawiony, Jordan K., Tuckey, Robert C.·2015·The Journal of Steroid Biochemistry and Molecular Biology
DOI 10.1016/j.jsbmb.2014.11.010PMC PMC4757911
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Abstract

CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Δ7steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage. Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1. Finally, CYP11A1-derived secosteroidal hydroxy-derivatives and Δ7steroids are biologically active when administered in vitro in a manner dependent on the structure of the compound and the lineage of the target cells, suggesting physiological roles for these metabolites. This article is part of a special issue entitled ‘SI: Steroid/Sterol signaling’.

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Crossref · 10.1016/j.jsbmb.2014.11.010

Cites

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Claims the paper makes

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  • Findingcitation

    Cultured human (HaCaT) epidermal keratinocytes and primary pig epidermal keratinocytes metabolize 7DHC to 7DHP without addition of exogenous 7DHC.

    “Final in vitro evidence that 7DHC is metabolized to 7DHP in the skin was obtained using cultured human (HaCaT) epidermal keratinocytes, and primary pig epidermal keratinocytes where products were detected without the addition of exogenous 7DHC [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] 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 2012 44 2003 2018 22877869 PMC3520099 source

      Not checked in the free run.

  • Findingcitation

    CYP11A1-dependent metabolism of vitamin D3 occurs in cells with relatively low expression of this enzyme, such as human and pig epidermal keratinocytes and colonic Caco-2 cells.

    “We also detected CYP11A1-dependent metabolism of D3 in cells with a relatively low expression of this enzyme such as human and pig epidermal keratinocytes [27], and colonic Caco-2 cells [103].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

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    • cites [103] Slominski AT Kim Li TKW 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 J. Steroid Biochem. Mol. Biol 2014 144PA 28 39 24176765 PMC4002668 source

      Not checked in the free run.

  • Findingcitation

    The adrenal gland and placenta supplied with exogenous vitamin D3 show higher production of 20(OH)D3 than 25(OH)D3.

    “Interestingly, the adrenal gland and placenta supplied with exogenous vitamin D3 showed higher production of 20(OH) D3 than 25(OH)D3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

  • Findingcitation

    Endogenous production of 20(OH)D3, 25(OH)D3, 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,25(OH)2D3, and 17,20,23(OH)3D3 was detected in HaCaT keratinocytes cultured in the presence of 5% serum without additional vitamin D3 supplements.

    “Also, endogenous production of 20(OH)D3, 25(OH) D3, 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,25(OH)2D3, and 17,20,23(OH)3D3 was detected in HaCaT keratinocytes cultured in the presence of 5% serum without additional supplements of D3 [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

  • Findingown data

    CYP11A1 hydroxylates the side chain of vitamin D3 and D2 in a sequential fashion: D3/D2 → 20S(OH)D3/D2 → (OH)nD3/D2.

    “Recently, we discovered that the CYP11A1 hydroxylates the side chain of D3 and D2 in a sequential fashion: D3/D2 → 20S(OH)D3/D2 → (OH)nD3/D2”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Slominski AT Kim Li TKW 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 J. Steroid Biochem. Mol. Biol 2014 144PA 28 39 24176765 PMC4002668 source

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  • May combine two claims. 51
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Findingcitation

    Ex utero incubations of human placentae and ex vivo incubations of pig adrenal glands with 7DHP result in its transformation to 7-dehydroprogesterone.

    “Ex-utero incubations of human placentae [8] and ex-vivo incubations of pig adrenal glands [23] with 7DHP resulted in its transformation to 7-dehydroprogesterone.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] 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 2012 44 2003 2018 22877869 PMC3520099 source

      Not checked in the free run.

    • cites [23] 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 2009 4 e4309 19190754 PMC2629546 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In pig adrenal gland ex vivo incubations, 7DHP is transformed to 17(OH)7DHP, but 21(OH)7DHP could not be detected.

    “In accordance with this, our studies with pig adrenal glands showed the transformation of 7DHP to 17(OH)7DHP during ex-vivo incubations, but 21(OH)7DHP could not be detected [23].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] 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 2009 4 e4309 19190754 PMC2629546 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Human CYP11A1 produces two other hydroxy-7DHC metabolites whose identity remains to be established, and neither corresponds to 20(OH)7DHC.

    “It should be noted that we also detected production of two other hydroxy-7DHC metabolites by human CYP11A1 of which the identity remains to be established [8]. Neither of them corresponded to 20 (OH)7DHC as demonstrated by their different retention times.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 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 2012 44 2003 2018 22877869 PMC3520099 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    CYP27B1 converts 20(OH)D2 to 1,20(OH)2D2, but this reaction is much less efficient than its conversion of 25(OH)D2 to 1,25(OH)2D2.

    “CYP27B1 also 1α-hydroxylates 20(OH)D2 producing 1,20 (OH)2D2, with an efficiency much lower than for the conversion of 25(OH)D2 to 1,25(OH)2D2 [112].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] 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 2011 300 C526 C541 21160030 PMC3063966 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    CYP11A1 does not epoxidize the C22-C23 double bond of vitamin D2, unlike ergosterol, which indicates that D2 binds differently in the enzyme active site.

    “Although the side chains of D2 and ergosterol are identical, no epoxidation of the double bond between C22 and C23 occurs for D2, indicating its different positioning in the active site.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Keratinocytes transform vitamin D3 to 20(OH)D3, 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3, with CYP27B1-dependent production of 1,20(OH)2D3 and 1,20,23(OH)3D3.

    “Thus, keratinocytes transformed D3 to 20(OH)D3, 22(OH) D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3, with CYP27B1-dependent production of 1,20(OH)2D3 and 1,20,23 (OH)3D3 also being observed [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A monohydroxyvitamin D3 compound with a retention time corresponding to 20(OH)D3 is present in human serum at a level 20 times lower than 25(OH)D3, indicating that 20(OH)D3 produced in these organs can enter the systemic circulation.

    “Detection of a monohydroxyvitamin D3 compound with a retention time corresponding to 20(OH) D3 in human serum, albeit at a level 20 times lower than that of 25 (OH)D3, indicates that 20(OH)D3 produced in these organs can enter the systemic circulation [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Caco-2 cells metabolize exogenous vitamin D3 to 20(OH)D3 as the predominant metabolite, with lesser production of 22(OH)D3 and 25(OH)D3, which are further metabolized to 20,23(OH)2D3, 1,20(OH)2D3, and 1,25(OH)2D3.

    “Caco-2 cells also metabolized exogenous vitamin D3 to 20 (OH)D3 as the predominant metabolite, with lesser production of 22(OH)D3 and 25(OH)D3. These were further metabolized to 20,23 (OH)2D3, 1,20(OH)2D3, and 1,25(OH)2D3 [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Slominski AT Kim Li TKW 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 J. Steroid Biochem. Mol. Biol 2014 144PA 28 39 24176765 PMC4002668 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Ex vivo and ex utero incubations of vitamin D3 with fragments of adrenal glands and human placentae demonstrate CYP11A1-catalyzed metabolism of vitamin D3 with 20(OH)D3 as the major metabolite, and less abundant products including 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3.

    “Most importantly, the in vivo studies represented by ex-vivo and ex-utero incubations of vitamin D3 with fragments of adrenal glands and human placentae, respectively, clearly demonstrate the CYP11A1-catalyzed metabolism of vitamin D3 with 20(OH) D3 being the major metabolite. Less abundant products included 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The adrenal gland and placenta express CYP27A1, CYP2R1, and CYP27B1, and convert vitamin D3 to 25(OH)D3, and 25(OH)D3 to 1,25(OH)2D3.

    “Both tissues were also shown to express CYP27A1, CYP2R1, and CYP27B1, and to convert vitamin D3 to 25(OH)D3, and 25(OH) D3 to 1,25(OH)2D3 [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

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

    Findingcitation

    Purified recombinant human CYP27B1 can 1α-hydroxylate 20(OH)D2.

    “The latter is consistent with the ability of purified recombinant human CYP27B1 to 1α-hydroxylate 20(OH)D2 [112].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] 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 2011 300 C526 C541 21160030 PMC3063966 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Ex-utero placentae metabolize vitamin D2 through CYP11A1 and also convert D2 to 25(OH)D2.

    “Placentae ex-utero, as well as metabolizing vitamin D2 via CYP11A1, also converted D2 to 25(OH) D2 [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    The products of these new pathways display biological activity when applied in vitro or in vivo, as do the corresponding vitamin D3 metabolites.

    “The physiological role of these new pathways remain to be established, but as for the corresponding D3 metabolites, products display biological activity when applied under in vitro or in vivo conditions (discussed in Section 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The conversion of D2 to 20(OH)D2, of 20(OH)D2 to 17,20(OH)2D2, and of 1α(OH)D2 to 1,20(OH)2D2 by placental and adrenal mitochondria is almost completely inhibited by 22R-hydroxycholesterol, implicating CYP11A1.

    “The involvement of CYP11A1 in the conversion of D2 to 20(OH) D2, 20(OH)D2 to 17,20(OH)2D2, and the prodrug 1α(OH)D2 to 1,20 (OH)2D2 was demonstrated by its almost complete inhibition by 22R-hydroxycholesterol when placental and adrenal mitochondria were used to run the reaction [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

    • Rests on an assumption: 22R-hydroxycholesterol specifically inhibits CYP11A1, so almost complete inhibition indicates that CYP11A1 mediates the reaction.

  • May combine two claims.

    Findingcitation

    Ex-utero placentae and isolated adrenal mitochondria 1α-hydroxylate both 25(OH)D2 to 1,25(OH)2D2 and 20(OH)D2 to 1,20(OH)2D2.

    “Placentae ex-utero and mitochondria isolated from adrenal glands not only 1α-hydroxylated 25(OH)D2 to 1,25(OH)2D2, but also 20(OH)D2 to 1,20(OH)2D2 [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Caco-2 cells produce significantly more 20(OH)D2 than 25(OH)D2, the opposite of what is observed in epidermal keratinocytes.

    “There was significantly higher production of 20(OH)D2 than 25(OH)D2 in Caco-2 cells that was opposite to what was observed in epidermal keratinocytes [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Human placentas, bovine adrenals, and human epithelial cells (epidermal keratinocytes and Caco-2 colon cells) transform vitamin D2 to 20(OH)D2, 17,20(OH)2D2, and 1,20(OH)2D2.

    “Importantly, using human placentas and bovine adrenals which express high levels of CYP11A1 [1,2], and human epithelial cells (epidermal keratinocytes and colonic Caco-2 cells) which express relatively low levels of this enzyme [14,15,111,113] we were able to demonstrate the in vivo (ex-vivo, ex-utero, and in cultured cells) transformation of D2 to 20(OH)D2,17,20(OH)2D2, and 1,20(OH)2D2 [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In placenta and Caco-2 cells, more 20(OH)D2 than 25(OH)D2 is produced from D2, whereas in human epidermal keratinocytes the amount of 20(OH)D2 is similar to or lower than that of 25(OH)D3.

    “Notably, the amount of 20(OH)D2 produced from D2 was higher than that of the initial product of the classical activation pathway, 25(OH)D2, in placenta and Caco-2 cells, but similar or lower than for 25(OH)D3 in human epidermal keratinocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Epithelial cells with low CYP11A1 activity, such as epidermal keratinocytes and Caco-2 cells, metabolize vitamin D2 through both the classical 25-hydroxylase-dependent pathway and the CYP11A1-dependent pathway, with the balance depending on cell type.

    “Epithelial cells expressing low CYP11A1 activity such as epidermal keratinocytes [14,83] and Caco-2 cells [111,113] metabolized D2 through the classical (25-hydroxylase-dependent) and CYP11A1-dependent pathways in a cell type dependent manner [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Novel secosteroids act as biased agonists at the vitamin D receptor, with selectivity for certain receptor-mediated effects, and can also interact with RORα and RORγ, presumably as inverse agonists.

    “Importantly, the novel secosteroids in addition to acting as biased agonists on the vitamin D receptor (showing selectivity for certain receptor mediated effects) [103,112,122], can also interact with RORα and γ, presumably acting as inverse agonists [123].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [103] Slominski AT Kim Li TKW 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 J. Steroid Biochem. Mol. Biol 2014 144PA 28 39 24176765 PMC4002668 source

      Not checked in the free run.

    • cites [112] 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 2011 300 C526 C541 21160030 PMC3063966 source

      Not checked in the free run.

    • cites [122] Kim T-K Wang J Janjetovic Z Chen J Tuckey RC Nguyen MN Tang EKY 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 2012 361 143 152 doi: http://dx.doi.org/10.1016/j.mce.2012.04.001 22546549 PMC3409337 source

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    • cites [123] Slominski AT Kim Takeda TKY 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 20,23-dihydroxyvitamin D FASEB J 2014 28 2775 2789 24668754 PMC4062828

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  • May combine two claims.

    Findingown data

    Photochemical opening of the B-ring of 7DHC, as occurs in vitamin D3, prevents side-chain cleavage even when the hydroxylation pattern would seem to permit it; no cleavage of 20,22(OH)2D3 is observed.

    “Photochemical opening of the B-ring of 7DHC, as seen in D3 (Fig. 3), prevents side chain cleavage from occurring, even when the pattern of hydroxylation would seem to make it possible as no cleavage of 20,22(OH)2D3 is observed.”
    Quote in the paperSubstantial claim

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    Findingcitation

    Pharmacologically administered 20(OH)D3 has antifibrotic activity in vitro and in vivo in bleomycin-induced scleroderma.

    “Pharmacologically administered 20(OH) D3 shows antifibrotic activities both in vitro [57,117,118] and in vivo in bleomycin induced scleroderma [118].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [57] 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 2013 5 7 19 24494038 PMC3897599 source

      Not checked in the free run.

    • cites [117] 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 2011 131 1167 1169 21228816 PMC3078214 source

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    • cites [118] 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 J. Clin. Endocrinol. Metab 2013 98 E298 E303 23295467 PMC3565109 source

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    Findingcitation

    Studies of SLOS patients show that under pathological conditions 7DHC can serve as a substrate for CYP11A1, and downstream Δ7 steroidal products may be responsible for some disease symptoms.

    “Studies of SLOS patients clearly show that under pathological conditions 7DHC can serve as a substrate for CYP11A1, with downstream Δ7 steroidal products possibly being responsible for some of the disease symptoms [58–61,63,64].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [58] Nowaczyk MJ Waye JS The Smith-Lemli-Opitz syndrome: a novel metabolic wayofunderstanding developmental biology, embryogenesis, and dysmorphology Clin. Genet 2001 59 375 386 11453964

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    • cites [59] Tint GS Irons M Elias ER Batta AK Frieden R Chen TS Salen G Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome N. Engl. J. Med 1994 330 107 113 8259166

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    • cites [60] Shackleton CH Roitman E Kelley R Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency Steroids 1999 64 481 490 10443904

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    • cites [61] Shackleton CH Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis Lipids 2012 47 1 12 21874273 PMC3564490

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    • cites [63] Marcos J Guo LW Wilson WK Porter FD Shackleton C The implications of 7-dehydrosterol-7-reductase deficiency (Smith-Lemli-Opitz syndrome) to neurosteroid production Steroids 2004 69 51 60 14715377

      Not checked in the free run.

    • cites [64] Shackleton C Roitman E Guo LW Wilson WK Porter FD Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-delta7-reductase deficiency (Smith-Lemli-Opitz syndrome) J. Steroid Biochem. Mol. Biol 2002 82 225 232 12477489

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    7DHC is a better substrate for CYP11A1 than cholesterol, while vitamins D3 and D2 are poorer substrates.

    “with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol.”
    • Also stated in: § 2.2. In vitro and in vivo models of 7DHC metabolism by CYP11A1 · hedged
      “In fact, human CYP11A1 has a slightly higher catalytic efficiency with 7DHC as a substrate (higher Kcat/Km) than with cholesterol, indicating that 7DHC can be used preferentially by the enzyme depending on its availability [8,14].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] 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 2012 44 2003 2018 22877869 PMC3520099 source

      Not checked in the free run.

    • cites [14] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C Tuckey RC A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin Eur. J. Biochem 2004 271 4178 4188 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [25] Tuckey RC W Li Zjawiony JK Zmijewski MA Nguyen MN Sweatman T Miller D Slominski A Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc FEBS J 2008 275 2585 2596 18410379 PMC2562691 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    7DHC, ergosterol, lumisterol 3, and vitamins D3 and D2 serve as substrates for CYP11A1.

    “Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [8] 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 2012 44 2003 2018 22877869 PMC3520099 source

      Not checked in the free run.

    • cites [14] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C Tuckey RC A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin Eur. J. Biochem 2004 271 4178 4188 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [22] Guryev O Carvalho RA Usanov S Gilep A Estabrook RW A pathway for the metabolism of vitamin D3: unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1) Proc. Natl. Acad. Sci. U. S. A 2003 100 14754 14759 14657394 PMC299797 source

      Not checked in the free run.

    • cites [23] 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 2009 4 e4309 19190754 PMC2629546 source

      Not checked in the free run.

    • cites [24] Slominski A Semak I Zjawiony J Wortsman J W Li Szczesniewski A Tuckey RC The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism FEBS J 2005 272 4080 4090 16098191 PMC2234577 source

      Not checked in the free run.

    • cites [25] Tuckey RC W Li Zjawiony JK Zmijewski MA Nguyen MN Sweatman T Miller D Slominski A Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc FEBS J 2008 275 2585 2596 18410379 PMC2562691 source

      Not checked in the free run.

    • cites [26] Tuckey RC Li W Shehabi HZ Janjetovic Z Nguyen MN Chen TK Kim 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 Metab. Dispos 2011 39 1577 1588 21677063 PMC3164270 source

      Not checked in the free run.

    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

    • cites [28] Nguyen MN Slominski A W Li Ng YR Tuckey RC Metabolism of vitamin D2-17,20,24-trihydroxyvitamin D2 by cytochrome p450scc (CYPHA1) Drug Metab. Dispos 2009 37 761 767 19116262 PMC2659330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    20-hydroxyvitamin D3 has been detected in human serum and the epidermis.

    “20-hydroxyvitamin D3 was detected in human serum and the epidermis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CYP11A1-dependent metabolism of 7DHC and vitamin D occurs in vivo, although its quantitative importance and physiological role remain to be established.

    “Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The activity of CYP11A1 is affected by substrate structure: sterols with steroidal or Δ7-steroidal structures undergo side chain cleavage following hydroxylations at C22 and C20, whereas vitamin D metabolism involves sequential hydroxylations starting at C20 without cleavage.

    “The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [1] Tuckey RC Progesterone synthesis by the human placenta Placenta 2005 26 273 281 15823613 source

      Not checked in the free run.

    • cites [14] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C Tuckey RC A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin Eur. J. Biochem 2004 271 4178 4188 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [22] Guryev O Carvalho RA Usanov S Gilep A Estabrook RW A pathway for the metabolism of vitamin D3: unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1) Proc. Natl. Acad. Sci. U. S. A 2003 100 14754 14759 14657394 PMC299797 source

      Not checked in the free run.

    • cites [10] Tuckey RC Nguyen MN Chen J Slominski AT Baldisseri DM Tieu EW Zjawiony JK W Li Human cytochrome P450scc (CYP11A1) catalyzes epoxide formation with ergosterol Drug Metab. Dispos 2012 40 436 444 22106170 PMC3286270 source

      Not checked in the free run.

    • cites [24] Slominski A Semak I Zjawiony J Wortsman J W Li Szczesniewski A Tuckey RC The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism FEBS J 2005 272 4080 4090 16098191 PMC2234577 source

      Not checked in the free run.

    • cites [25] Tuckey RC W Li Zjawiony JK Zmijewski MA Nguyen MN Sweatman T Miller D Slominski A Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc FEBS J 2008 275 2585 2596 18410379 PMC2562691 source

      Not checked in the free run.

    • cites [26] Tuckey RC Li W Shehabi HZ Janjetovic Z Nguyen MN Chen TK Kim 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 Metab. Dispos 2011 39 1577 1588 21677063 PMC3164270 source

      Not checked in the free run.

    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

    • cites [28] Nguyen MN Slominski A W Li Ng YR Tuckey RC Metabolism of vitamin D2-17,20,24-trihydroxyvitamin D2 by cytochrome p450scc (CYPHA1) Drug Metab. Dispos 2009 37 761 767 19116262 PMC2659330 source

      Not checked in the free run.

    • cites [29] 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 FEBS J 2006 273 2891 2901 16817851 PMC1893115 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Catalytic activity of CYP11A1 on non-traditional substrates such as vitamin D and ergosterol does not result in side chain cleavage, but involves sequential hydroxylations of the side chain including at C17.

    “Importantly, catalytic activity on non-traditional substrates such as vitamin D and ergosterol does not result in side chain cleavage, but involves sequential hydroxylations of the side chain including at C17 [[10,24–30], and see below].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [10] Tuckey RC Nguyen MN Chen J Slominski AT Baldisseri DM Tieu EW Zjawiony JK W Li Human cytochrome P450scc (CYP11A1) catalyzes epoxide formation with ergosterol Drug Metab. Dispos 2012 40 436 444 22106170 PMC3286270 source

      Not checked in the free run.

    • cites [24] Slominski A Semak I Zjawiony J Wortsman J W Li Szczesniewski A Tuckey RC The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism FEBS J 2005 272 4080 4090 16098191 PMC2234577 source

      Not checked in the free run.

    • cites [25] Tuckey RC W Li Zjawiony JK Zmijewski MA Nguyen MN Sweatman T Miller D Slominski A Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc FEBS J 2008 275 2585 2596 18410379 PMC2562691 source

      Not checked in the free run.

    • cites [26] Tuckey RC Li W Shehabi HZ Janjetovic Z Nguyen MN Chen TK Kim 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 Metab. Dispos 2011 39 1577 1588 21677063 PMC3164270 source

      Not checked in the free run.

    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

    • cites [28] Nguyen MN Slominski A W Li Ng YR Tuckey RC Metabolism of vitamin D2-17,20,24-trihydroxyvitamin D2 by cytochrome p450scc (CYPHA1) Drug Metab. Dispos 2009 37 761 767 19116262 PMC2659330 source

      Not checked in the free run.

    • cites [29] 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 FEBS J 2006 273 2891 2901 16817851 PMC1893115 source

      Not checked in the free run.

    • cites [30] Slominski A Semak I Zjawiony J Wortsman J Gandy MN Li J Zbytek B W Li Tuckey RC Enzymatic metabolism of ergosterol by cytochrome p450scc to biologically active 17alpha,24-dihydroxyergosterol Chem. Biol 2005 12 931 939 16125105 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Molecular modeling using the crystal structure of human CYP11A1 bound to 20R,22R-dihydroxycholesterol showed that 7DHC docked with the C22 hydrogen closer to the heme iron than the C20 hydrogen, consistent with initial hydroxylation at C22 being favored.

    “7DHC was docked to the crystal structure of CYP11A1 in place of the 20R,22R-dihydroxycholesterol. It showed that the C22 hydrogen was closer to the heme iron than the hydrogen at C20, consistent with initial hydroxylation at C22 being favored.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] 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 2012 44 2003 2018 22877869 PMC3520099 source

      Not checked in the free run.

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

    Premisecitation

    7DHC is an immediate precursor of cholesterol in the Kandutsch-Russel pathway, and desmosterol is the immediate precursor in the Bloch pathway.

    “If reduction of the Δ24-bond occurs early, cholesterol is synthesized via the Kandutsch–Russel pathway (favored in most tissues) using 7-dehydrocholesterol as the immediate precursor of cholesterol.”
    • Also stated in: § 2.1. Overview of cholesterol synthesis · plain
      “In the Bloch pathway reduction of the Δ24-bond occurs as the last enzymatic step that forms cholesterol from desmosterol.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [50] Frantz DI Jr Schroepfer GJ Sterol biosynthesis Annu. Rev. Biochem 1967 36 691 726 18257735

      Not checked in the free run.

    • cites [53] Waterham HR Wanders RJ Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome Biochim. Biophys. Acta 2000 1529 340 356 11111101

      Not checked in the free run.

    • cites [54] Bae SH Paik YK Cholesterol biosynthesis from lanosterol: development of a novel assay method and characterization of rat liver microsomal lanosterol delta 24-reductase Biochem. J 1997 326 Pt 2 609 616 9291139 PMC1218712

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  • May combine two claims.

    Premisecitation

    The reaction mechanism of cholesterol side chain cleavage by CYP11A1 involves initial hydroxylation at C22 to 22R-hydroxycholesterol, then hydroxylation at C20 to 20R,22R-dihydroxycholesterol, followed by oxidative cleavage of the C20-C22 bond to produce pregnenolone.

    “The reaction involves initial hydroxylation at C22 producing 22R-hydroxycholesterol, then subsequent repositioning of the side chain in the active site resulting in a second hydroxylation at C20, producing 20R,22R-dihydroxycholesterol. This is followed by oxidative cleavage of the C20—C22 bond producing pregnenolone [1–3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Tuckey RC Progesterone synthesis by the human placenta Placenta 2005 26 273 281 15823613 source

      Not checked in the free run.

    • cites [2] Miller WL Auchus RJ The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders Endocr. Rev 2011 32 81 151 21051590 PMC3365799 source

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    • cites [3] Burstein S Middleditch BS Gut M Mass spectrometric study of the enzymatic conversion of cholesterol to (22R)-22-hydroxycholesterol, (20R,22R)-20,22-dihydroxycholesterol, and pregnenolone, and of (22R)-22-hydroxycholesterol to the lgycol and pregnenolone in bovine adrenocortical preparations. Mode of oxygen incorporation J. Biol. Chem 1975 250 9028 9037 1238395

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In classical steroidogenic tissues, CYP11A1 activity is substrate limited, and increased cholesterol delivery causes a corresponding increase in the rate of pregnenolone synthesis.

    “In the classical pathway of cholesterol side chain cleavage, CYP11A1 activity is substrate limited and increased rates of cholesterol delivery cause a corresponding increase in the rate of pregnenolone synthesis.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [2] Miller WL Auchus RJ The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders Endocr. Rev 2011 32 81 151 21051590 PMC3365799 source

      Not checked in the free run.

    • cites [11] Miller WL Boser HS Early steps in steroidogenesis: intracellular cholesterol trafficking J. Lipid Res 2011 52 2111 2135 21976778 PMC3283258

      Not checked in the free run.

    • cites [12] Miller WL Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter Biochim. Biophys. Acta 2007 1771 663 676 17433772

      Not checked in the free run.

    • cites [13] Hu J Zhang Z Shen WJ Azhar S Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones Nutr. Metab. (Lond.) 2010 7 47 20515451 PMC2890697

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    • cites [14] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C Tuckey RC A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin Eur. J. Biochem 2004 271 4178 4188 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [15] Slominski A Zbytek B Nikolakis G Manna PR Skobowiat C Zmijewski M W Li Janjetovic Z Postlethwaite A Zouboulis CC Tuckey RC Steroidogenesis in the skin: implications for local immune functions J. Steroid Biochem. Mol. Biol 2013 137 107 123 23435015 PMC3674137 source

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  • May combine two claims.

    Premisecitation

    Purified human CYP11A1 acts on ergosterol, with no cleavage of the side chain due to the C22 double bond; the C22=C23 double bond undergoes epoxidation to produce 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol, and the other major product is 22-keto-23-hydroxy-22,23-dihydroergosterol.

    “Purified human CYP11A1 acts on the fungal membrane sterol, ergosterol, also available through the diet. No cleavage of the side chain occurs due to the presence of the double bond at C22. Rather, the C22=C23 double bond undergoes epoxidation to produce 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol. The other major product is 22-keto-23-hydroxy-22,23-dihydroergosterol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Tuckey RC Nguyen MN Chen J Slominski AT Baldisseri DM Tieu EW Zjawiony JK W Li Human cytochrome P450scc (CYP11A1) catalyzes epoxide formation with ergosterol Drug Metab. Dispos 2012 40 436 444 22106170 PMC3286270 source

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  • May combine two claims.

    Premisecitation

    CYP21A2 does not use 7DHP as a substrate, similar to its inability to act on pregnenolone.

    “CYP21A2 does not appear to use 7DHP as a substrate, similar to its inability to act on pregnenolone [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Sushko TA Gilep AA Yantsevich AV Usanov SA Role of microsomal steroid hydroxylases in Delta7-steroid biosynthesis Biochemistry (Mosc.) 2013 78 282 289 23586722

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  • May combine two claims.

    Premisecitation

    Human and bovine CYP11A1 cleave the side chain of cholesterol sulfate, with lower catalytic efficiency than cholesterol for purified enzymes, but at higher rates than cholesterol by CYP11A1 in ovarian mitochondria due to more rapid movement to the inner mitochondrial membrane.

    “Human and bovine CYP11A1 have been shown to cleave the side chain of cholesterol sulfate, with lower catalytic efficiency than cholesterol for the purified enzymes [71], but at higher rates than cholesterol by CYP11A1 in ovarian mitochondria, due to its more rapid movement to the inner mitochondrial membrane [72].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Tuckey RC Lawrence J Cameron KJ Side-chain cleavage of cholesterol esters by human cytochrome P-450(scc) J. Steroid Biochem. Mol. Biol 1996 58 605 610 8918988

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    • cites [72] Tuckey RC Side-chain cleavage of cholesterol sulfate by ovarian mitochondria J. Steroid Biochem. Mol. Biol 1990 37 121 127 2242345

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  • May combine two claims.

    Premisecitation

    17α,24-Dihydroxyergosterol is biologically active on cultured human skin cells, inhibiting DNA synthesis.

    “17α,24-Dihydroxyergosterol is biologically active on cultured human skin cells, inhibiting DNA synthesis, but the other products remain to be tested, as does any in vivo function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Slominski A Semak I Zjawiony J Wortsman J Gandy MN Li J Zbytek B W Li Tuckey RC Enzymatic metabolism of ergosterol by cytochrome p450scc to biologically active 17alpha,24-dihydroxyergosterol Chem. Biol 2005 12 931 939 16125105 source

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  • May combine two claims.

    Premisecitation

    Bovine CYP11A1 acts on ergosterol with a different product profile than human CYP11A1, with major products including 24-hydroxyergosterol and 17α,24-dihydroxyergosterol.

    “Bovine CYP11A1 also acts on ergosterol but the product profile varies compared to that seen for human CYP11A1, with major products including 24-hydroxyergosterol and 17α,24-dihydroxyergosterol [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Slominski A Semak I Zjawiony J Wortsman J Gandy MN Li J Zbytek B W Li Tuckey RC Enzymatic metabolism of ergosterol by cytochrome p450scc to biologically active 17alpha,24-dihydroxyergosterol Chem. Biol 2005 12 931 939 16125105 source

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  • May combine two claims.

    Premisecitation

    In Smith-Lemli-Opitz syndrome, there is increased accumulation of 7DHC and production of 7DHP and its downstream steroid metabolites.

    “The above findings are consistent with a well described phenomenon of increased accumulation of 7DHC, and production of 7DHP and its downstream steroid metabolites in Smith-Lemli-Opitz syndrome (SLOS), characterized by a deficiency of 7DHC Δ-reductase [58–61].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [58] Nowaczyk MJ Waye JS The Smith-Lemli-Opitz syndrome: a novel metabolic wayofunderstanding developmental biology, embryogenesis, and dysmorphology Clin. Genet 2001 59 375 386 11453964

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    • cites [59] Tint GS Irons M Elias ER Batta AK Frieden R Chen TS Salen G Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome N. Engl. J. Med 1994 330 107 113 8259166

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    • cites [60] Shackleton CH Roitman E Kelley R Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency Steroids 1999 64 481 490 10443904

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    • cites [61] Shackleton CH Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis Lipids 2012 47 1 12 21874273 PMC3564490

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  • May combine two claims.

    Premisecitation

    CYP11A1 initially hydroxylates lumisterol 3 at C22 or C24; 22-hydroxylumisterol is then hydroxylated at C20 producing 20,22-dihydroxylumisterol 3, and some undergoes cleavage to pregnalumisterol.

    “CYP11A1 initially hydroxylates lumisterol 3 at C22 or C24. 22-Hydroxylumisterol is then hydroxylated at C20 producing 20,22-dihydroxylumisterol 3 and some of this undergoes hydroxylation at other sites while some undergoes cleavage to pregnalumisterol [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Tuckey RC Slominski AT Y Cheng C Chen J K Kim T Xiao M W Li Lumisterol is metabolized by CYP11A1: discovery of a new pathway Int. J. Biochem. Cell Biol 2014 55 24 34 25130438 PMC4252613 source

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  • May combine two claims.

    Premisecitation

    Pregnalumisterol and some synthetic hydroxylumisterol 3 derivatives exhibit biological activity.

    “Pregnalumisterol and some synthetic hydroxylumisterol 3 derivatives exhibit biological activity [76,77] further suggesting that metabolism of lumisterol by CYP11A1 in the skin may produce metabolites with physiological activity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [76] 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.) 2011 4 1485 1494 21733837

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    • cites [77] 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 2010 5 e9907 20360850 PMC2845617 source

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  • May combine two claims.

    Premisecitation

    The major pathway of vitamin D3 metabolism by CYP11A1 is D3→20(OH)D3→20,23(OH)2D3→17,20,23(OH)3D3, with D3→20(OH)D3 + 22(OH)D3→20,22(OH)2D3 as a minor pathway.

    “These studies defined the conversions: D3→20(OH)D3→20,23(OH)2D3→17,20,23(OH)3D3 as the major pathway of vitamin D3 metabolism by CYP11A1 with D3 → 20(OH)D3 + 22(OH)D3 → 20,22(OH)2D3 as a minor pathway [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Slominski AT Kim Li TKW 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 J. Steroid Biochem. Mol. Biol 2014 144PA 28 39 24176765 PMC4002668 source

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  • May combine two claims.

    Premisecitation

    Conversion of vitamin D3 to 20(OH)D3 by CYP11A1 is less efficient (lower Kcat/Km) than hydroxylation of cholesterol, with bovine CYP11A1 metabolizing vitamin D3 more efficiently than the human enzyme.

    “However, the conversion of vitamin D3 to 20(OH)D3 by CYP11A1 is less efficient (lower Kcat/Km) than hydroxylation of cholesterol by this enzyme [25], supported by molecular modeling [7], with bovine CYP11A1 metabolizing vitamin D3 more efficiently than the human enzyme [7,25,27].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Strushkevich N MacKenzie F Cherkesova T Grabovec I Usanov S Park HW Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system Proc. Natl. Acad. Sci. U. S. A 2011 108 10139 10143 21636783 PMC3121847 source

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    • cites [25] Tuckey RC W Li Zjawiony JK Zmijewski MA Nguyen MN Sweatman T Miller D Slominski A Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc FEBS J 2008 275 2585 2596 18410379 PMC2562691 source

      Not checked in the free run.

    • cites [27] 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 J 2012 26 3901 3915 22683847 PMC3425822 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The products of CYP11A1 action on vitamin D can be further hydroxylated by CYP27B1, CYP27A1, and CYP24A1, providing an alternative to the classical pathway, although its physiological importance remains to be established.

    “The products can be further hydroxylated by CYP27B1, CYP27A1, and CYP24A1 (reviewed in [103], and see below), which is an alternative to the classical pathway (see above), although its physiological importance remains to be established.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Slominski AT Kim Li TKW 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 J. Steroid Biochem. Mol. Biol 2014 144PA 28 39 24176765 PMC4002668 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP11A1 does not metabolize 25-hydroxyvitamin D3, indicating that hydroxylation at C25 protects the secosteroid against side chain hydroxylation by CYP11A1, and therefore this enzyme does not compete with CYP27B1 for activation of 25(OH)D3.

    “Importantly, CYP11A1 does not metabolize 25-hydroxyvitamin D3 indicating that hydroxylation at C25 protects the secosteroid against hydroxylation of the side chain by CYP11A1 [24] and therefore, that this enzyme does not compete with CYP27B1 for activation of 25(OH)D3 [103].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Slominski A Semak I Zjawiony J Wortsman J W Li Szczesniewski A Tuckey RC The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism FEBS J 2005 272 4080 4090 16098191 PMC2234577 source

      Not checked in the free run.

    • cites [103] Slominski AT Kim Li TKW 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 J. Steroid Biochem. Mol. Biol 2014 144PA 28 39 24176765 PMC4002668 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The excellent docking score of 8-dehydrocholesterol and the presence of Δ8-steroids in body fluids of SLOS patients predict that 8-dehydrocholesterol is also a CYP11A1 substrate that undergoes side-chain cleavage like 7-DHC and cholesterol.

    “An excellent docking score for 8-dehydrocholesterol in conjunction with the presence of Δ8-steroids in body fluids of SLOS patients [60,61,63,64], predicts that it is also a substrate for CYP11A1 that undergoes cleavage of its side chain similar to 7-DHC and cholesterol.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [60] Shackleton CH Roitman E Kelley R Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency Steroids 1999 64 481 490 10443904

      Not checked in the free run.

    • cites [61] Shackleton CH Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis Lipids 2012 47 1 12 21874273 PMC3564490

      Not checked in the free run.

    • cites [63] Marcos J Guo LW Wilson WK Porter FD Shackleton C The implications of 7-dehydrosterol-7-reductase deficiency (Smith-Lemli-Opitz syndrome) to neurosteroid production Steroids 2004 69 51 60 14715377

      Not checked in the free run.

    • cites [64] Shackleton C Roitman E Guo LW Wilson WK Porter FD Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-delta7-reductase deficiency (Smith-Lemli-Opitz syndrome) J. Steroid Biochem. Mol. Biol 2002 82 225 232 12477489

      Not checked in the free run.

    • Rests on an assumption: Docking scores from molecular modeling predict whether a compound is a CYP11A1 substrate.

  • May combine two claims.

    Interpretationcitation

    Ex-vivo, ex-utero, and cell-culture studies indicate that vitamin D2 can be metabolized in vivo in tissues expressing CYP11A1, that its products can be further modified by CYP27B1, and that the resulting metabolite profiles are tissue- and cell-type specific.

    “In summary, ex-vivo, ex-utero, and cell culture studies indicate that D2 can be metabolized in vivo in tissues expressing CYP11A1, with further modification of products by CYP27B1, with metabolite profiles that are tissues- and cell-type specific [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Slominski AT Kim TK Shehabi HZ Tang EK Benson HA Semak I Lin Z Yates CR Wang J W Li Tuckey RC In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes Caco-2 colon cells and the adrenal gland Mol. Cell. Endocrinol 2014 383 181 192 24382416 PMC3997123

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    7-Dehydrodesmosterol, lathosterol, and tachysterol have excellent docking scores, suggesting they could also be CYP11A1 substrates in tissues that express the enzyme and produce sufficient concentrations of these compounds.

    “Interestingly, 7-dehydrodesmosterol and lathosterol intermediates of the cholesterol biosynthetic pathway, as well as tachysterol which is a product of UVB transformation of pre-D, have excellent docking scores suggesting that they could also serve as substrates for CYP11A1 in tissues expressing this enzyme and producing sufficient concentrations of these compounds.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Docking scores from molecular modeling predict whether a compound is a CYP11A1 substrate.

  • May combine two claims.

    Interpretationreasoning

    The CYP11A1 active site can accommodate a range of steroids, but these substrates are all structurally close to cholesterol, the largest variation being the secosteroids with a broken B-ring.

    “Thus, the active site of CYP11A1 can accommodate a range of steroids but it should be emphasized that they are all closely related to cholesterol in structure, with the biggest structural variation being for the secosteroids which contain a broken B-ring.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The structure of the substrate affects both the regio-selectivity of hydroxylation and the catalytic efficiency of CYP11A1.

    “The structure of the substrate affects both the regio-selectivity of hydroxylation and the catalytic efficiency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Ergosterol does not undergo side-chain cleavage because the C22=C23 double bond in its side chain makes hydroxylation at C22 unfavorable, despite the presence of a Δ7 double bond.

    “Despite the presence of a Δ7 double bond in ergosterol it does not undergo cleavage due to the C22=C23 double bond in the side chain making it unfavorable to undergo hydroxylation at C22.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CYP11A1 can generate several intermediates and products that are biologically active in a context-dependent manner when administered exogenously, but their physiological roles remain to be defined.

    “It can generate several intermediates and products that are biologically active in a context dependent manner when administered exogenously, but for which physiological roles remain to be defined.”
    Quote in the paperSubstantial claim
52 of 52

  • The authors state this as an assumption.

    All CYP11A1 forms convert cholesterol to pregnenolone to initiate de novo steroidogenesis.

    “All are assumed to convert cholesterol to pregnenolone to initiate de novo steroidogenesis.”

  • The paper relies on this without support.

    Docking scores from molecular modeling predict whether a compound is a CYP11A1 substrate.

    “We observed excellent docking scores for several compounds listed in Table 1 that were comparable to cholesterol or hydroxycholesterol substrates.”
    “An excellent docking score for 8-dehydrocholesterol in conjunction with the presence of Δ8-steroids in body fluids of SLOS patients [60,61,63,64], predicts that it is also a substrate for CYP11A1 that undergoes cleavage of its side chain similar to 7-DHC and cholesterol.”

  • The paper relies on this without support.

    22R-hydroxycholesterol specifically inhibits CYP11A1, so almost complete inhibition indicates that CYP11A1 mediates the reaction.

    “The involvement of CYP11A1 in the conversion of D2 to 20(OH) D2, 20(OH)D2 to 17,20(OH)2D2, and the prodrug 1α(OH)D2 to 1,20 (OH)2D2 was demonstrated by its almost complete inhibition by 22R-hydroxycholesterol when placental and adrenal mitochondria were used to run the reaction [9].”
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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • D2 product has conflicting hydroxyl counts

    Minor

    The reaction sequence labels the 17,20,24-hydroxylated D2 product as having two hydroxyl groups, while the next paragraph labels the same product as having three.

  • D3 product keeps a dihydroxy label after another hydroxylation

    Minor

    The stated CYP27B1 reaction adds a hydroxyl group at position 1 to 20,23-dihydroxyvitamin D3, but labels the resulting three-position product as dihydroxy. Elsewhere the paper labels that product as trihydroxy.

  • D3 pathway gives inconsistent notation for its final product

    Minor

    The tissue-pathway summary labels its final 17,20,23-hydroxylated product with "(OH)32," whereas the earlier pathway labels the same product with "(OH)3."

3 of 3

Cites

Flagged first, then by citations

2 of the 126 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

  1. Zhu, 2012, Vitamin D 25-hydroxylase – four decades of searching, are we there yet?, Arch. Biochem. Biophys., 523, 30, 10.1016/j.abb.2012.01.013 · DOI
  2. Zehnder, 2001, Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase, J. Clin. Endocrinol. Metab., 86, 888
  3. Sakaki, 2005, Metabolism of vitamin D3 by cytochromes P450, Front. Biosci., 10, 119
  4. Tuckey, 2011, Production of 22-hydroxy metabolites of vitamin D3 by cytochrome p450scc (CYP11A1) and analysis of their biological activities on skin cells, Drug Metab. Dispos., 39, 1577, 10.1124/dmd.111.040071 · DOI · Paper page
  5. Tieu, 2012, Metabolism of cholesterol, vitamin D3 and 20-hydroxyvitamin D3 incorporated into phospholipid vesicles by human CYP27A1, J. Steroid Biochem. Mol. Biol., 129, 163, 10.1016/j.jsbmb.2011.11.012 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Slominski, A. T., Li, W., Kim, T.-K., Semak, I., Wang, J., Zjawiony, J. K., & Tuckey, R. C.
Affiliations
  • University of Tennessee Health Science Center (US)
  • Belarusian State University (BY)
  • University of Mississippi (US)
  • The University of Western Australia (AU)
Corresponding author
  • Slominski, Andrzej T.
  • Tuckey, Robert C.
ORCID
Venue
The Journal of Steroid Biochemistry and Molecular Biology
Publisher
Elsevier BV
Published
2015-07
Volume
151
Pages
25-37
ISSN
0960-0760 (ISSN-L)
DOI
10.1016/j.jsbmb.2014.11.010
PMC
PMC4757911
OpenAlex
W1966916284
Semantic Scholar
e45086fb38972c20b400df40d2a6eb44a9b81394
Cited by
292
References
126
Citations by year
2026: 12 · 2025: 11 · 2024: 29 · 2023: 28 · 2022: 28 · 2021: 37 · 2020: 36 · 2019: 24 · 2018: 19 · 2017: 20 · 2016: 28 · 2015: 19 · 2014: 1
FWCI
2.17
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)
  • BSU Digital Library (Belarusian State University) (submittedVersion, cc-by)
Funders
NIH (R01AR052190, R02AR052190, R21AR066505-01A1, 1R01AR056666-01A2)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
CYP11A1, pregnenolone synthesis, cholesterol, 7-dehydrocholesterol, vitamin D metabolism, secosteroids, desmosterol, campesterol, β-sitosterol, ergosterol, lumisterol, Smith-Lemli-Opitz syndrome, substrate specificity, enzyme crystal structure, molecular modeling, epidermal keratinocytes, adrenal gland, placenta, steroid hormone signaling
MeSH terms
Animals, Cholecalciferol, Cholesterol Side-Chain Cleavage Enzyme, Dehydrocholesterols, Ergocalciferols, Humans, Sterols

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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