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Cited by 217Aldose Reductase and TaurineSteroid Chemistry and BiochemistryHormonal Regulation and Hypertension

Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism

Open access
Rižner, Tea Lanišnik, Penning, Trevor M.·2014·Steroids
DOI 10.1016/j.steroids.2013.10.012PMC PMC3870468
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Abstract

Human aldo-keto reductases AKR1C1-AKR1C4 and AKR1D1 play essential roles in the metabolism of all steroid hormones, the biosynthesis of neurosteroids and bile acids, the metabolism of conjugated steroids, and synthetic therapeutic steroids. These enzymes catalyze NADPH dependent reductions at the C3, C5, C17 and C20 positions on the steroid nucleus and side-chain. AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents, while AKR1D1 acts as the sole Δ(4)-3-ketosteroid-5β-reductase (steroid 5β-reductase) in humans. AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and trans-activation, they also regulate the amount of neurosteroids that can modulate the activity of GABAA and NMDA receptors. As such they are involved in the pre-receptor regulation of nuclear and membrane bound receptors. Altered expression of individual AKR1C genes is related to development of prostate, breast, and endometrial cancer. Mutations in AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency.

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Written from the paper’s full text.

TL;DR

This review summarizes the roles of human aldo-keto reductase family 1 (AKR1) enzymes AKR1C1–AKR1C4 and AKR1D1 in steroid hormone, neurosteroid, conjugated steroid, synthetic steroid, and bile acid metabolism. It emphasizes their pre-receptor control of nuclear and membrane receptor ligands and their altered expression or mutation in prostate, breast, and endometrial cancer, sexual development dysgenesis, and bile-acid deficiency.

Key findings

  • AKR1C1–AKR1C4 act as NADPH-dependent 3-keto, 17-keto, and 20-ketosteroid reductases with varying efficiencies, while AKR1D1 is the sole human Δ4-3-ketosteroid-5β-reductase; AKR1D1 catalyzes reduction of C18, C19, C21, and C27 Δ4-ketosteroids.
  • AKR1C3 has the highest catalytic efficiency among AKR1C enzymes for reduction of Δ4-androstene-3,17-dione to testosterone and for estrone to 17β-estradiol (KM = 9 μM, kcat = 0.068 mM−1; kcat/KM = 76 min−1 mm−1). AKR1C2 has the highest catalytic efficiency as a 3-ketosteroid reductase for 5α-DHT to 3α-Diol, while AKR1C1 mainly forms 3β-Diol.
  • Altered AKR1C expression is linked to cancer: AKR1C3 is the most up-regulated steroidogenic enzyme in castration-resistant prostate cancer and soft-tissue metastases; AKR1C3 immunoreactivity is positive in 77%–82% of primary prostate adenocarcinoma. In breast cancer, AKR1C3 protein was detected in 56% of cancer specimens and 92% of nonmalignant adjacent tissues from 50 patients.
  • Inherited AKR1D1 mutations cause bile-acid deficiency, with seven point mutations listed (Leu106Phe, Pro133Arg, Gly223Glu, Pro198Leu, Asp241Val, Arg261Cys, Arg266Glu); AKR1C2 and AKR1C4 mutations were identified in two Swiss families with disordered sexual dysgenesis.

Methods

  • Narrative review of published literature on human AKR1 enzymes, integrating enzyme kinetics, crystal structures, expression data, disease associations, and mutation analyses.
  • The paper reports that 37 crystal structures of human AKR1C enzymes in complex with different ligands had been solved as of May 5, 2013, and cites studies using recombinant enzymes, transfected cell lines, microarrays, immunohistochemistry, and patient mutation data.
  • Main analysis is qualitative synthesis; no systematic search strategy, meta-analysis, or primary experimental dataset is described.

Limitations

  • The paper states that more extensive studies on AKR1 metabolism of synthetic steroids are still required, that physiological and pathophysiological roles are not known in every instance, and that SNP databases are not always complete and accurate.
  • It notes that cellular levels of particular isoforms should be considered when judging physiological significance, and that it is not known whether all truncated transcript variants are translated into active proteins.
  • Evident from the text: this is a narrative review without a stated systematic search or quantitative synthesis, and it includes several unpublished observations (e.g., Jin and Penning, unpublished data; Hevir and Lanišnik Rižner, unpublished data; N. Beranič and T. Lanišnik Rižner, unpublished data).

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Integrity signals

Registry

Crossref · 10.1016/j.steroids.2013.10.012

Cites

108 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 179 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The later reactions in bile acid biosynthesis proceed with higher catalytic efficiency than double bond reduction.

    “The later reactions proceed with a higher catalytic efficiency than double bond reduction (Jin and Penning, unpublished data).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jin and Penning, unpublished data

      Not checked in the free run.

  • Findingcitation

    Unpublished data suggest that AKR1C3 probably contributes to androgen biosynthesis.

    “By contrast AKR1C3 probably has a role in androgen biosynthesis (Hevir and Lanišnik Rižner, unpublished data).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hevir and Lanišnik Rižner, unpublished data

      Not checked in the free run.

  • Premisecitation

    AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying degrees.

    “AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Penning TM Burczynski ME Jez JM Hung CF Lin HK Ma H Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones Biochem J 2000 351 67 77 10998348 PMC1221336 source

      Not checked in the free run.

  • Premisenone given

    AKR1C1 through AKR1C4 and AKR1D1 are essential for human steroid hormone metabolism.

    “Human aldo-keto reductases AKR1C1-AKR1C4 and AKR1D1 play essential roles in the metabolism of all steroid hormones”
    Quote in the paperSubstantial claim
  • Premisenone given

    These enzymes catalyze NADPH-dependent reductions at positions C3, C5, C17 and C20 of the steroid nucleus and side chain.

    “These enzymes catalyze NADPH dependent reductions at the C3, C5, C17 and C20 positions on the steroid nucleus and side-chain.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 67
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingcitation

    Unpublished data indicate that AKR1C3 is unlikely to be important for estrogen biosynthesis in endometrial cancer because estrogens there are mainly produced from estrone sulfate.

    “The unpublished data suggests that AKR1C3 does not play an important role in estrogen biosynthesis in endometrial cancer as estrogens are mainly derived from estrone-sulfate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hevir and Lanišnik Rižner, unpublished data

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In peripheral tissues, AKR1C enzymes act as 3-keto and 17-ketosteroid reductases to form 5α-DHT or to inactivate it to 3α-Diol or 3β-Diol.

    “In peripheral tissues, AKR1C enzymes act as 3-keto and 17-ketosteroid reductases to catalyze either the formation of the most potent androgen 5α-dihydrotestosterone (5α-DHT) or its inactivation to yield the inactive androgens 5α-androstane-3α,17β-diol (3α-Diol) or 5α-androstane-3β,17β-diol (3β-Diol)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Lanišnik Rižner T Lin HK Peehl DM Steckelbroeck S Bauman DR Penning TM Human type 3 3a-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells Endocrinology 2003 144 2922 2932 12810547 source

      Not checked in the free run.

    • cites [16] Steckelbroeck S Jin Y Gopishetty S Oyesanmi B Penning TM Human cytosolic 3α-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3β-hydroxysteroid dehydrogenase activity J Biol Chem 2004 279 10784 10795 14672942 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The A/B cis configuration introduces a 90° bend and amphipathic properties essential for emulsification of fats and cholesterol.

    “This configuration introduces a 90° bend into the planar steroid and introduces amphipathic properties into the sterol which is essential for emulsification of fats and cholesterol”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Russel DW Setchell KDR Bile acid biosynthesis Biochemistry 1992 31 4737 4749 1591235 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    AKR1 enzymes control the concentrations of active nuclear receptor ligands and their receptor occupancy and trans-activation.

    “AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and trans-activation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Human AKR1 family enzymes catalyze either biosynthesis or inactivation of steroid hormones, bile acids and neurosteroids and thereby regulate their activity.

    “Human enzymes from the AKR1 family catalyze either the biosynthesis of steroid hormones, bile acids and neurosteroids, or their inactivation and thus regulate activity and action of these mediators”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Penning TM Human hydroxysteroid dehydroganses and pre-receptor regulation: insights into inhibitor design and evaluation J Steroid Biochem Mol Biol 2011 125 46 56 21272640 PMC3104102 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SDR and AKR enzymes catalyze NAD(P)H-dependent oxidoreductions at C3, C5, C11, C17 and C20 and act as various hydroxysteroid dehydrogenases and reductases.

    “The SDR and AKR enzymes catalyze NAD(P)H dependent oxidoreductions and act at the C3, C5, C11, C17 and C20 positions of the steroid nucleus and side-chain and function as 3α/β-hydroxysteroid dehydrogenases (HSDs), 5β-reductases, 11β-HSDs, 17β-HSDs and 20α-HSDs, respectively”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Penning TM Human hydroxysteroid dehydroganses and pre-receptor regulation: insights into inhibitor design and evaluation J Steroid Biochem Mol Biol 2011 125 46 56 21272640 PMC3104102 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1D1 is expressed mainly in liver, consistent with its role in bile acid biosynthesis.

    “AKR1D1 is expressed mainly in liver as might be expected by its role in bile acid biosynthesis”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Iyer RB Binstock JM Schwartz IS Gordon GG Weinstein BI Southern AL Human hepatic cortisol reductase activities: enzymatic properties and substrate specificities of cytosolic cortisol Δ4–5-β reductase and dihydrocortisol-3-α-oxidoreductase(s) Steroids 1990 55 495 500 2075615 source

      Not checked in the free run.

    • cites [26] Kondo KH Kai MH Setoguchi Y Eggertsen G Sjoblom P Setoguchi T Cloning and expression of cDNA of human Δ4–3-oxosteroid 5β-reductase and substrate specificity of the expressed enzyme Eur J Biochem 1994 219 375 363 7508385 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With high-turnover substrates, NADP+ release limits the reaction rate, and release is a two-step process involving isomerization from a tight to a loose E.NADP+ complex.

    “However, with substrates with high turnover numbers the rate of release of the NADP+ cofactor places an upper limit on the rate of reaction. The release of the NADP+ cofactor is a two step process in which an isomerisation event occurs to convert a E.NADP+ tight complex to form a E.NADP+ loose complex”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Ratnam K Ma H Penning TM The arginine 276 anchor for NADP(H) dictates fluorescence kinetic transients in 3α-hydroxysteroid dehydrogenase, a representative aldo-keto reductase Biochemistry 1999 38 7856 64 10387026 source

      Not checked in the free run.

    • cites [28] Jin Y Penning TM Multiple steps determine the overall rate of the reduction of 5α-dihydrotestosterone catalyzed by human type 3 3α-hydroxysteroid dehydrogenase: implications for the elimination of androgens Biochemistry 2006 45 13054 63 17059222 PMC2597410 source

      Not checked in the free run.

    • cites [29] Cooper WC Jin Y Penning TM Elucidation of a complete kinetic mechanism for a mammalian hydroxysteroid dehydrogenase (HSD) and identification of all enzyme forms on the reaction coordinate: the example of rat liver 3α-HSD (AKR1C9) J Biol Chem 2007 282 33484 93 17848571 source

      Not checked in the free run.

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

    Premisecitation

    AKR1D1 has an (α/β)8 barrel structure with cofactor and steroid substrate bound at the C-terminal end of the β-sheets.

    “The AKR1D1 enzyme has the typical (α/β)8 barrel structure of the AKR superfamily with cofactor and the steroid substrate bound at the C-terminal end of the β-sheets”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Di Constanzo L Drury JE Penning TM Christianson DW Crystal structure of human liver Δ4–3-ketosteroid 5β-reductase (AKR1D1) and implications for substate binding and catalysis J Biol Chem 2008 283 16830 16839 18407998 PMC2423251 source

      Not checked in the free run.

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

    Premisenone given

    Phase I steroid biosynthetic enzymes include cytochrome P450 monooxygenases, SDR oxidoreductases and AKR oxidoreductases; 5α-reductases belong to the polyprenol reductase family.

    “Phase I steroid biosynthetic enzymes include: monooxygenases from the cytochrome P450s superfamily (CYP), and oxidoreductases from the short-chain dehydrogenase reductase (SDR) and the aldo-keto reductase (AKR) superfamilies. An outlier are the 5α-reductases which belong to the polyprenol reductase family.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    AKR1C enzymes share 84% to 98% amino acid sequence identity, and AKR1C1 and AKR1C2 differ by only seven residues.

    “AKR1C enzymes share a high percentage of amino-acid sequence identity that ranges from 84% to 98%. In particular AKR1C1 and AKR1C2, differ by only seven amino-acid residues.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Phase II conjugating enzymes include sulfotransferases, UDP glucuronosyl transferases and catechol-O-methyl transferases.

    “The phase II conjugating enzymes include the sulfotransferases (SULTs), UDP glucuronosyl transferases (UGTs) and catechol-O-methyl transferases (COMT).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After the chemical step, steroid product leaves followed by oxidized cofactor, and different steps can be rate-limiting depending on substrate.

    “Following the chemical step, steroid product then leaves followed by the oxidized cofactor. Different steps of the reaction can be rate-limiting depending upon the substrate.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Ratnam K Ma H Penning TM The arginine 276 anchor for NADP(H) dictates fluorescence kinetic transients in 3α-hydroxysteroid dehydrogenase, a representative aldo-keto reductase Biochemistry 1999 38 7856 64 10387026 source

      Not checked in the free run.

    • cites [28] Jin Y Penning TM Multiple steps determine the overall rate of the reduction of 5α-dihydrotestosterone catalyzed by human type 3 3α-hydroxysteroid dehydrogenase: implications for the elimination of androgens Biochemistry 2006 45 13054 63 17059222 PMC2597410 source

      Not checked in the free run.

    • cites [29] Cooper WC Jin Y Penning TM Elucidation of a complete kinetic mechanism for a mammalian hydroxysteroid dehydrogenase (HSD) and identification of all enzyme forms on the reaction coordinate: the example of rat liver 3α-HSD (AKR1C9) J Biol Chem 2007 282 33484 93 17848571 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hydroxysteroid product stereochemistry can be inverted by the ketosteroid being pushed across the pocket or bound upside down.

    “stereochemistry of the hydroxysteroid product can be inverted by either the ketosteroid being pushed across the steroid pocket by steric forces or the ketosteroid can be bound upside down”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Steckelbroeck S Jin Y Oyesanmi B Kloosterboer HJ Penning TM Tibolone is metabolized by the 3α/3β-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a Δ5(10)-3-ketosteroid Mol Pharmacol 2004 66 1702 11 15383625 source

      Not checked in the free run.

    • cites [19] Jin Y Penning TM Molecular docking simulations of steroid substrates into human cytosolic hydroxysteroid dehydrogenases (AKR1C1 and AKR1C2): insights into positional and stereochemical preferences Steroids 2006 71 380 91 16455123 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C enzymes function in vivo as 3-keto, 17-keto and 20-ketosteroid reductases, forming 3α/β, 17β and 20α hydroxy metabolites and metabolizing many natural and synthetic steroids.

    “AKR1C enzymes (AKR1C1-AKR1C4) function in vivo as 3-keto-, 17-keto- and 20-ketosteroid reductases to form 3α/β, 17β- and 20α-hydroxy-metabolites to varying extents and thus metabolize a broad spectrum of natural and synthetic therapeutic steroids”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Penning TM Burczynski ME Jez JM Hung CF Lin HK Ma H Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones Biochem J 2000 351 67 77 10998348 PMC1221336 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1 enzymes act on conjugated steroids and on synthetic therapeutic steroids.

    “In addition, these enzymes act on conjugated steroids and synthetic steroids used as therapeutics”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [10] Jin Y Duan L Lee SH Kloosterboer HJ Blair IA Penning TM Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism J Biol Chem 2009 284 10013 22 19218247 PMC2665056 source

      Not checked in the free run.

    • cites [11] Beranič N Gobec S Lanišnik Rižner T Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3 Chem Biol Interact 2011 191 227 233 21182831 source

      Not checked in the free run.

    • cites [12] Jin Y Duan L Chen M Penning TM Kloosterboer HJ Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo-keto reductase superfamily J Steroid Biochem Mol Biol 2012 129 139 144 22210085 PMC3303946 source

      Not checked in the free run.

    • cites [13] Beranič N Brožič P Brus B Sosič I Gobec S Lanišnik Rižner T Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: Potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins J Steroid Biochem Mol Biol 2012 130 16 25 22245609 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C enzymes are expressed in different tissues, while AKR1C4 is mainly liver-specific.

    “These enzymes are expressed in different tissues, while AKR1C4 is mainly liver specific”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Penning TM Burczynski ME Jez JM Hung CF Lin HK Ma H Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones Biochem J 2000 351 67 77 10998348 PMC1221336 source

      Not checked in the free run.

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

    Premisecitation

    The conserved catalytic tetrad is Asp50, Tyr55, Lys84 and His117, with Tyr55 acting as a general acid-base.

    “The conserved catalytic tetrad resides at the base of the barrel and consists of Asp50, Tyr55, Lys84 and His117, where Tyr55 acts as a general acid-base”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Penning TM Human hydroxysteroid dehydroganses and pre-receptor regulation: insights into inhibitor design and evaluation J Steroid Biochem Mol Biol 2011 125 46 56 21272640 PMC3104102 source

      Not checked in the free run.

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

    Premisecitation

    A proposed mechanism for AKR1D1 5β-reduction has Tyr58 as general acid and Glu120 as a superacid facilitating enolization of the Δ4 double bond.

    “A mechanism of AKR1D1 catalyzed 5β-reduction has been proposed, in which Tyr58 acts as a general acid and Glu120 facilitates enolization of the Δ4 double bond by acting as a superacid”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Chen M Drury JE Penning TM Substrate specificity and inhibitor analyses of human steroid 5b-reductase (AKR1D1) Steroids 2011 76 484 490 21255593 PMC3056882 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In AKR1 proteins the cofactor binds in a conserved manner across the β-barrel lip, and the steroid lies perpendicular to the cofactor.

    “In each of the AKR1 proteins the cofactor binds in a conserved manner across the lip of the β-barrel, while the steroid lies perpendicular to the cofactor.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Penning TM Human hydroxysteroid dehydroganses and pre-receptor regulation: insights into inhibitor design and evaluation J Steroid Biochem Mol Biol 2011 125 46 56 21272640 PMC3104102 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    AKR1 enzymes preferentially act as reductases in vivo because they have nanomolar NADPH Kd values, a high cellular NADPH/NADP+ ratio, and NADPH inhibits NAD+-dependent oxidation at low micromolar concentrations.

    “These enzymes preferably act as reductases in vivo since they have Kd values for NADPH in the nanomolar range, there is a high NADPH/NADP+ ratio within cells and NADPH inhibits the NAD+ dependent oxidation reactions at low μM concentrations”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Lanišnik Rižner T Lin HK Peehl DM Steckelbroeck S Bauman DR Penning TM Human type 3 3a-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells Endocrinology 2003 144 2922 2932 12810547 source

      Not checked in the free run.

    • cites [16] Steckelbroeck S Jin Y Gopishetty S Oyesanmi B Penning TM Human cytosolic 3α-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3β-hydroxysteroid dehydrogenase activity J Biol Chem 2004 279 10784 10795 14672942 source

      Not checked in the free run.

    • cites [17] Penning TM Bryns MC Steroid hormone transforming aldo-keto reductases and cancer Ann N Y Acad Sci 2009 1155 33 42 19250190 PMC3038333 source

      Not checked in the free run.

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

    Premisecitation

    AKR1C enzymes share the TIM barrel fold, with three large loops at the back of the barrel defining substrate specificity.

    “AKR1C enzymes share the protein fold in common with other members of the superfamily, which is the triose phosphate isomerase (TIM) barrel characterized by an alternating arrangement of α-helix and β-strand to form a β-barrel. At the back of the barrel three large loops exist which define substrate specificity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Penning TM Human hydroxysteroid dehydroganses and pre-receptor regulation: insights into inhibitor design and evaluation J Steroid Biochem Mol Biol 2011 125 46 56 21272640 PMC3104102 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSDs from the SDR and AKR superfamilies differ in protein fold, hydride-transfer stereochemistry and kinetic mechanism but share a conserved catalytic mechanism.

    “HSDs from the SDR and AKR superfamilies differ in their protein folds, stereochemistry of hydride transfer and kinetic mechanism but share a common catalytic mechanism that has been evolutionary conserved”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Penning TM Human hydroxysteroid dehydroganses and pre-receptor regulation: insights into inhibitor design and evaluation J Steroid Biochem Mol Biol 2011 125 46 56 21272640 PMC3104102 source

      Not checked in the free run.

    • cites [9] Bennett MJ Schlegel BP Jez JM Penning TM Lewis M Structure of 3α-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+ Biochemistry 1996 35 10702 11 8718859 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Further reduction of 5β-DHT to etiocholanone is catalyzed by AKR1C enzymes, with AKR1C4 most efficient, followed by AKR1C2, AKR1C3 and AKR1C1.

    “Further reduction of 5β-DHT to etiocholanone is catalyzed by the AKR1C enzymes, where AKR1C4 is the most efficient enzyme, followed by AKR1C2, AKR1C3 and AKR1C1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Jin Y Mesaros C Blair IA Penning TM Stereospecific reduction of 5β-reduced steroids by human ketosteroid reductases of the AKR (aldo-keto reductase) superfamily: role of AKR1C1-AKR1C4 in the metabolism of testosterone and progesterone via the 5β-reductase pathway Biochem J 2011 437 53 61 21521174 PMC3825703 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    AKR1C1 can regulate cellular allopregnanolone concentrations by preventing its formation from progesterone and by catalyzing its inactivation.

    “AKR1C1 can regulate the cellular concentrations of allopregnanolone by preventing its formation from progesterone and by catalyzing allopregnanolone inactivation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Subsequent 3-ketosteroid reduction by AKR1C enzymes yields four stereoisomeric tetrahydrosteroids that can be further conjugated by phase II enzymes.

    “Subsequent 3-ketosteroid reduction by the AKR1C enzymes yields four stereoisomeric tetrahydrosteroids which can be further conjugated by phase II enzymes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    AKR1D1 catalyzes 5β-reduction of 7α-hydroxy-4-cholestene-3-one and 7α,12α-dihydroxy-4-cholestene-3-one to their respective 5β products, and AKR1C4 reduces the 3-keto group.

    “AKR1D1 catalyzes 5β-reduction of bile acid precursors 7α-hydroxy-4-cholestene-3-one and 7α,12α-dihydroxy-4-cholestene-3-one to yield 7α-hydroxy-5β-cholestan-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one, respectively and AKR1C4 catalyzes the further reduction of 3-keto group”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Russel DW Setchell KDR Bile acid biosynthesis Biochemistry 1992 31 4737 4749 1591235 source

      Not checked in the free run.

    • cites [23] Chen M Drury JE Penning TM Substrate specificity and inhibitor analyses of human steroid 5b-reductase (AKR1D1) Steroids 2011 76 484 490 21255593 PMC3056882 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C1 and AKR1C2 prefer sulfate over bulky glucuronide conjugates, with AKR1C2 being the more efficient enzyme.

    “By contrast, AKR1C1 and AKR1C2 prefer sulfate to bulky glucuronide conjugates where AKR1C2 is the more efficient enzyme”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Jin Y Duan L Lee SH Kloosterboer HJ Blair IA Penning TM Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism J Biol Chem 2009 284 10013 22 19218247 PMC2665056 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C1, AKR1C2 and AKR1C3 form mainly 3β-hydroxy-5α-androstane-17β-glucuronide, whereas AKR1C4 preferentially forms the corresponding 3α-stereoisomer.

    “AKR1C1, AKR1C2 and AKR1C3 form mainly 3β-hydroxy-5α-androstane-17β-glucuronide whereas AKR1C4 preferentially forms the corresponding 3α-stereoisomer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Jin Y Duan L Lee SH Kloosterboer HJ Blair IA Penning TM Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism J Biol Chem 2009 284 10013 22 19218247 PMC2665056 source

      Not checked in the free run.

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

    Premisecitation

    The classical pathway of 5α-DHT formation converts Δ4-androstene-3,17-dione to testosterone and then reduces it to 5α-DHT by SRD5A1 and SDR5A2.

    “The conversion of Δ4-androstene-3,17-dione to testosterone and its subsequent reduction to 5α-DHT by SRD5A1 and SDR5A2 is known as the “classical pathway” of 5α-DHT formation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Auchus RJ The backdoor pathway to dihydrotestosterone Trends Endocrinol Metab 2004 15 432 438 15519890 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among AKR1C enzymes, AKR1C4 has by far the highest catalytic efficiency for reduction of 5α-DHT-17β-glucuronide or sulfate, while AKR1C3 has a low kcat for this reaction.

    “Among AKR1C enzymes, AKR1C4 has by far the highest catalytic efficiency for reduction of 5α-DHT-17β-glucuronide or sulfate. AKR1C3 has a low kcat for this reaction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Jin Y Duan L Lee SH Kloosterboer HJ Blair IA Penning TM Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism J Biol Chem 2009 284 10013 22 19218247 PMC2665056 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Kinetic data suggest that in brain AKR1C2 forms the potent neurosteroid allopregnanolone, while AKR1C1 is involved in its inactivation.

    “The kinetic data thus suggest that in brain AKR1C2 catalyzes formation of the potent neurosteroid allopregnanolone, while AKR1C1 is involved in its inactivation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Usami N Yamamoto T Shintani S Higaki Y Ishikura S Katagiri Y Hara A Substrate specificity of human 3(20)α-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines Biol Pharm Bull 2002 25 441 445 11995921 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C1 forms mainly 3β-Diol, a potent ERβ agonist with anti-proliferative effects.

    “AKR1C1 forms mainly 3β-Diol, a potent agonist of ERβ which exerts anti-proliferative effects”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Steckelbroeck S Jin Y Gopishetty S Oyesanmi B Penning TM Human cytosolic 3α-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3β-hydroxysteroid dehydrogenase activity J Biol Chem 2004 279 10784 10795 14672942 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C2 has the highest catalytic efficiency as a 3-ketosteroid reductase and reduces 5α-DHT to 3α-Diol.

    “AKR1C2 has the highest catalytic efficiency as a 3-ketosteroid reductase and catalyzes reduction of 5α-DHT to 3α-Diol”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Lanišnik Rižner T Lin HK Peehl DM Steckelbroeck S Bauman DR Penning TM Human type 3 3a-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells Endocrinology 2003 144 2922 2932 12810547 source

      Not checked in the free run.

    • cites [16] Steckelbroeck S Jin Y Gopishetty S Oyesanmi B Penning TM Human cytosolic 3α-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3β-hydroxysteroid dehydrogenase activity J Biol Chem 2004 279 10784 10795 14672942 source

      Not checked in the free run.

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

    Premisecitation

    Subsequent bile acid biosynthesis steps include side chain oxidation and truncation and conjugation with taurine or glycine.

    “Subsequent steps in bile acid biosynthesis include side chain oxidation and truncation, and conjugation of the bile acid with taurine or glycine”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Russel DW Setchell KDR Bile acid biosynthesis Biochemistry 1992 31 4737 4749 1591235 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C3 is much less efficient as a 3-ketosteroid reductase and converts 5α-DHT mainly to 3α-Diol.

    “AKR1C3 is much less efficient as a 3-ketosteroid reductase and converts 5α-DHT mainly to 3α-Diol”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Steckelbroeck S Jin Y Gopishetty S Oyesanmi B Penning TM Human cytosolic 3α-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3β-hydroxysteroid dehydrogenase activity J Biol Chem 2004 279 10784 10795 14672942 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    AKR1C2 and AKR1C4 play critical roles in the backdoor androgen pathway, in which 5α-reduction occurs at the level of pregnanes.

    “In this manner AKR1C2 and AKR1C4 enzymes play a critical role in the “backdoor pathway” of androgen formation in which 5α-reduction occurs at the levels of the pregnanes”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Auchus RJ The backdoor pathway to dihydrotestosterone Trends Endocrinol Metab 2004 15 432 438 15519890 source

      Not checked in the free run.

    • cites [35] Sharifi N Auchus RJ Steroid biosynthesis and prostate cancer Steroids 2012 77 719 726 22503713 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In liver and some peripheral tissues such as placenta and myometrium, AKR1D1 reduces progesterone to 5β-DHP, while SRD5A1 and SRD5A2 form 5α-DHP.

    “In liver and some peripheral tissues (e.g. placenta and myometrium) AKR1D1 catalyzes reduction of progesterone to 5β-dihydroprogesterone (5β-DHP) while the 5α-reductases SRD5A1 and SRD5A2 form 5α-dihydroprogesterone (5α-DHP)”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [23] Chen M Drury JE Penning TM Substrate specificity and inhibitor analyses of human steroid 5b-reductase (AKR1D1) Steroids 2011 76 484 490 21255593 PMC3056882 source

      Not checked in the free run.

    • cites [38] Traish AM 5α-Reductases in human physiology: an unfolding story Endocr Pract 2012 18 965 75 23246684 source

      Not checked in the free run.

    • cites [39] Mitchell BF Mitchell JM Chowdhury J Tougas M Engelen SME Senff N Metabolites of progesterone and the pregnane X receptor: A novel pathway regulating uterine contractility in pregnancy? Am J Obstet Gynecol 2005 192 1304 1315 15846226 source

      Not checked in the free run.

    • cites [40] Sheehan PM Rice GE Moses EK Brennecke SP 5β-Dihydroprogesterone and steroid 5β-reductase decrease in association with human parturition at term Mol Hum Reprod 2005 11 495 501 16123077 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C3 also reduces 5α-androstane-3,17-dione to 5α-DHT, bypassing testosterone, and reduces androsterone to 3α-Diol.

    “AKR1C3 also reduces 5α-androstane-3,17-dione to 5α-DHT which by-passes testosterone (this is known as the alternative pathway to DHT); and reduces androsterone to 3α-Diol”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Auchus RJ The backdoor pathway to dihydrotestosterone Trends Endocrinol Metab 2004 15 432 438 15519890 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C1, AKR1C2 and AKR1C4 have high catalytic efficiencies for 5α-DHP reduction; AKR1C1 preferentially forms 20α-hydroxy-5α-pregnane-3-one and AKR1C2 preferentially forms allopregnanolone.

    “AKR1C1, AKR1C2 and AKR1C4 have high catalytic efficiencies for 5α-DHP reduction, where AKR1C1 preferentially forms 20α-hydroxy-5α-pregnane-3-one and AKR1C2 preferentially forms allopregnanolone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Higaki Y Usami N Shintani S Ishikura S El-Kabbani O Hara A Selective and potent inhibitors of human 20α-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone Chem Biol Interact 2003 143–144 503 513 12604236 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C enzymes act on conjugated steroids, suggesting an alternative route in which the steroid is conjugated first at the 17β-position and then reduced at the 3-position.

    “Recently AKR1C enzymes were shown to act on conjugated steroids (Table 3) [10], which suggested an alternative route where the steroid is conjugated first at the 17β-position and then reduced at the 3-position.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Jin Y Duan L Lee SH Kloosterboer HJ Blair IA Penning TM Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism J Biol Chem 2009 284 10013 22 19218247 PMC2665056 source

      Not checked in the free run.

    • Rests on an assumption: Phase I and phase II enzymes act sequentially in steroid metabolism.

  • May combine two claims.

    Premisecitation

    AKR1C3 is the most efficient enzyme for estrone reduction, with KM = 9 μM, kcat = 0.068 mM−1 and kcat/KM = 76 min−1 mm−1.

    “AKR1C3 is the most efficient enzyme for this reaction (KM = 9 μM, kcat = 0.068 mM−1; kcat/KM = 76 min−1 mm−1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Penning TM Burczynski ME Jez JM Hung CF Lin HK Ma H Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones Biochem J 2000 351 67 77 10998348 PMC1221336 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Allopregnanolone is a potent allosteric modulator of GABAA, while 5α-pregnane-3α,20α-diol is less neuroactive.

    “Allopregnanolone is a potent allosteric modulator of GABAA, while 5α-pregnane-3α,20α-diol is less neuroactive”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Belelleli D Lambert JJ Neurosteroids: endogenous regulators of the GABAA receptor Nature Rev Neuroscience 2005 6 565 575 15959466 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Human AKR1 enzymes convert weak receptor ligands to potent ligands or eliminate them, thereby controlling levels of potent ligands that occupy and trans-activate nuclear receptors in endocrine target tissues.

    “Human AKR1 enzymes catalyze the conversion of either weak ligands to form potent ligands for nuclear receptors or they are involved in the elimination of these ligands. In this manner AKR1 enzymes control the levels of potent ligands that can occupy and trans-activate nuclear receptors within endocrine target tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    AKR1 enzymes control active androgen concentrations and regulate androgen receptor occupancy and trans-activation in the prostate.

    “AKR1 enzymes control concentrations of active androgens and regulate the occupancy and trans-activation of androgen receptor (AR) in the prostate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Immunohistochemical staining showed a significant increase in AKR1C2 total scores and AKR1C2 scores in stromal cells in ovarian endometriosis.

    “but a significant increase was seen in AKR1C2 total scores and AKR1C2 scores in stromal cells [94].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Hevir N Vouk K Sinkovec J Ribič-Pucelj M Rižner TL Aldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis Chem Biol Interact 2011 191 217 26 21232532 source

      Not checked in the free run.

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

    Premisecitation

    Ito et al. reported higher AKR1C3 staining in endometrial hyperplasia and endometrial cancer but provided no experimental data for the stained sections.

    “At the cellular level, Ito et al. [92] reported higher AKR1C3 staining in endometrial hyperplasia and EC, but showed no experimental data for the stained sections.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Ito K Utsunomiya H Suzuki T Saitou S Akahira J Okamura K 17β-hydroxysteroid dehydrogenases in human endometrium and its disorders Mol Cell Endocrinol 2006 248 136 40 16406263

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Formation of 3β-hydroxytibolone is preferred over 3α-hydroxytibolone because the 5(10)-ene and 17α-ethinyl group allow the steroid to flip at the active site relative to 5α-DHT.

    “The formation of the 3β-hydroxymetabolite is preferred over the 3α-hydroxymetabolite because the presence of the 5(10)-ene and 17α-ethinyl group enables the steroid to be flipped over at the active-site relative to 5α-DHT.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Steckelbroeck S Jin Y Oyesanmi B Kloosterboer HJ Penning TM Tibolone is metabolized by the 3α/3β-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a Δ5(10)-3-ketosteroid Mol Pharmacol 2004 66 1702 11 15383625 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1 enzymes are involved in the metabolism of tibolone, norethynodrel, dydrogesterone, budesonide and flunisolide.

    “AKR1 enzymes are involved in the metabolism of tibolone and the progestins, norethynodrel and dydrogesterone (Table 4, Figure 6), as well as the synthetic glucocorticoids budesonide and flunisolide”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Beranič N Gobec S Lanišnik Rižner T Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3 Chem Biol Interact 2011 191 227 233 21182831 source

      Not checked in the free run.

    • cites [12] Jin Y Duan L Chen M Penning TM Kloosterboer HJ Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo-keto reductase superfamily J Steroid Biochem Mol Biol 2012 129 139 144 22210085 PMC3303946 source

      Not checked in the free run.

    • cites [13] Beranič N Brožič P Brus B Sosič I Gobec S Lanišnik Rižner T Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: Potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins J Steroid Biochem Mol Biol 2012 130 16 25 22245609 source

      Not checked in the free run.

    • cites [18] Steckelbroeck S Jin Y Oyesanmi B Kloosterboer HJ Penning TM Tibolone is metabolized by the 3α/3β-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a Δ5(10)-3-ketosteroid Mol Pharmacol 2004 66 1702 11 15383625 source

      Not checked in the free run.

    • The authors state this as an assumption: Many synthetic steroids contain a Δ4 or 3-keto,20-keto structural motif and are substrates for AKR1 enzymes.

  • May combine two claims.

    Premisecitation

    Androgens stimulate migration and survival of endometrial stromal cells.

    “Androgens have been shown to stimulate endometrial stromal migration and survival [91]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Marshall E Lowrey J MacPherson S Maybin JA Collins F Critchley HO In silico analysis identifies a novel role for androgens in the regulation of human endometrial apoptosis J Clin Endocrinol Metab 2011 96 E1746 55 21865353 PMC3380091 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mainly liver-specific AKR1C4 forms the 3α-hydroxy-metabolite, which is the major circulating tibolone metabolite.

    “By contrast the mainly liver specific AKR1C4 forms the 3α-hydroxy-metabolite which is the major metabolite found in the circulation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Steckelbroeck S Jin Y Oyesanmi B Kloosterboer HJ Penning TM Tibolone is metabolized by the 3α/3β-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a Δ5(10)-3-ketosteroid Mol Pharmacol 2004 66 1702 11 15383625 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dydrogesterone is metabolized to the active 20α-hydroxy-metabolite by AKR1C1 and AKR1C2 and acts as a micromolar inhibitor of AKR1C3.

    “Dydrogesterone is metabolized to the active 20α-hydroxy-metabolite, 20α-hydroxy-9β,10α-pregna-4,6-diene-3-one by AKR1C1 and AKR1C2 enzymes and acts as μM inhibitor of AKR1C3”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Beranič N Gobec S Lanišnik Rižner T Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3 Chem Biol Interact 2011 191 227 233 21182831 source

      Not checked in the free run.

    • cites [13] Beranič N Brožič P Brus B Sosič I Gobec S Lanišnik Rižner T Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: Potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins J Steroid Biochem Mol Biol 2012 130 16 25 22245609 source

      Not checked in the free run.

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

    Interpretationnone given

    Inherited or SNP allelic variants in AKR1 genes may affect metabolism of exogenous and endogenous steroids.

    “Inherited or SNP allelic variants in AKR1 genes may affect the metabolism of exogenous and endogenous steroids”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    AKR1C3 reduces Δ4-androstene-3,17-dione to testosterone (Kd = 10−9 M for AR) and 5α-androstane-3,17-dione to 5α-DHT (Kd = 10−10 M for AR).

    “AKR1C3 catalyzes the reduction of Δ4-androstene-3,17-dione to form the potent androgen testosterone (Kd = 10−9 M for AR) and the reduction of 5α-androstane-3,17-dione to yield the most potent androgen 5α-DHT (Kd =10−10 M for the AR).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Lanišnik Rižner T Lin HK Peehl DM Steckelbroeck S Bauman DR Penning TM Human type 3 3a-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells Endocrinology 2003 144 2922 2932 12810547 source

      Not checked in the free run.

    • cites [16] Steckelbroeck S Jin Y Gopishetty S Oyesanmi B Penning TM Human cytosolic 3α-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3β-hydroxysteroid dehydrogenase activity J Biol Chem 2004 279 10784 10795 14672942 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Longer incubation times were needed to measure AKR1C3's weak 3-ketosteroid reductase activity for the glucuronide conjugate, and the observed stereoselectivity change may relate to its epimerase activity.

    “As longer incubation times were required to measure the weak 3-ketosteroid reductase activity of AKR1C3 for the glucuronide conjugate, the observed change in stereoselectivity may be related to its epimerase activity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Jin Y Duan L Lee SH Kloosterboer HJ Blair IA Penning TM Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism J Biol Chem 2009 284 10013 22 19218247 PMC2665056 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AKR1C1 and AKR1C2 form 3β-hydroxytibolone and are responsible for prodrug activation in peripheral tissues, where the 3β-hydroxymetabolite activates ERα/β.

    “AKR1C1 and AKR1C2 form 3β-hydroxytibolone and are responsible for pro-drug activation in peripheral tissues where the 3β-hydroxymetabolite activates ERα/β.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Steckelbroeck S Jin Y Oyesanmi B Kloosterboer HJ Penning TM Tibolone is metabolized by the 3α/3β-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a Δ5(10)-3-ketosteroid Mol Pharmacol 2004 66 1702 11 15383625 source

      Not checked in the free run.

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

    Interpretationreasoning

    Such variants may contribute to development of pathophysiological processes.

    “and may also contribute to the development of pathophysiological processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Budesonide and flunisolide can be metabolized by AKR1D1 and AKR1C enzymes and also act as inhibitors of AKR1 enzymes.

    “The inhaled synthetic corticosteroids budesonide and flunisolide used in anti-inflammatory drug therapy in asthma patients can be metabolized by AKR1D1 and AKR1C enzymes. These steroids also act as inhibitors of AKR1 enzymes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Jin Y Activities of aldo-keto reductase 1 enzymes on two inhalded corticosteroids: implications for the pharmacological effects of inhaled corticosteroids Chem Biol Interact 2011 191 234 238 21276783 PMC3100382 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Budesonide is a more potent inhibitor of liver AKR1D1 and AKR1C4 than flunisolide, suggesting that this inhibition might contribute to budesonide's undesirable systemic effects.

    “budesonide was a more potent inhibitor of the AKR1D1 and AKR1C4 enzymes in the liver than flunisolide suggesting that this inhibition might contribute to the undesirable systemic effects of budesonide”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Jin Y Activities of aldo-keto reductase 1 enzymes on two inhalded corticosteroids: implications for the pharmacological effects of inhaled corticosteroids Chem Biol Interact 2011 191 234 238 21276783 PMC3100382 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These reactions act as molecular switches controlling androgen receptor ligand occupancy and likely influence prostate cancer progression.

    “These reactions thus represent molecular switches that can control ligand occupancy of the AR and likely influence prostate cancer progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The authors observed AKR1C2 and AKR1C4 expression in fetal testes and concluded these enzymes are needed for fetal 5α-DHT synthesis via the backdoor pathway and normal genital development.

    “The authors observed AKR1C2 and AKR1C4 expression in fetal testes thus they concluded that these enzymes are needed for fetal 5α-DHT synthesis via the backdoor pathway and normal development of the genitalia [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Flueck C Meyer Boeni M Pandey AV Kempna P Miller WL Schoenle EJ Why boys will be boys: Two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation Am J Hum Genetics 2011 89 201 218 21802064 PMC3155178 source

      Not checked in the free run.

    • Rests on an assumption: Normal male fetal sexual differentiation depends on synthesis of 5α-DHT for development of male external genitalia.

  • May combine two claims.

    Premiseown data

    These five are Phe46Tyr in AKR1C2 (MAF 0.051), His5Gln and Lys104Asn in AKR1C3 (MAF 0.428 and 0.132), and Ser145Cys and Leu311Val in AKR1C4 (MAF 0.104).

    “These correspond to Phe46Tyr in AKR1C2 with a MAF = 0.051; His5Gln and Lys104Asn in AKR1C3 with MAF of 0.428 and 0.132, respectfully; and Ser145Cys and Leu311Val in AKR1C4, both with MAF of 0.104.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Bioinformatics predicted that 8.3% of biallelic coding SNPs in dbSNP represent single nucleotide differences.

    “Based on a bioinformatics approach it has been predicted that 8.3% of biallelic, coding SNPs in the dbSNP database represent single nucleotide differences (SNDs) [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Musumeci L Arthur JW Cheung FSG Hoque A Lippman S Reichardt JKV Single nucleotide differences (SNDs) in the dbSNP database may lead to errors in genotyping and haplotyping studies Human Mutation 2009 31 67 73 19877174 PMC2797835 source

      Not checked in the free run.

    • Rests on an assumption: SNP databases can be incomplete and contain inaccuracies.

  • May combine two claims.

    Premisecitation

    HEK293 expression of Pro198Leu and Gly223Glu mutants showed lower enzymatic activity and expression levels.

    “and lower enzymatic activity and expression levels of both Pro198Leu and Gly223Glu.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Drury JE Mindnich R Penning TM Characterization of disease-related 5β-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency J Biol Chem 2010 32 24529 24537 20522910 PMC2915689 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Lower AKR1C2 activity in Phe46Tyr carriers may increase 5α-DHT levels and may stimulate prostate cell proliferation.

    “Lower AKR1C2 activity in the Phe46Tyr carriers may increase 5α-DHT levels and may thus stimulate prostate cell proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    AKR1 enzymes contribute importantly to processing androgens, estrogens, progesterone, glucocorticoids, neurosteroids, and conjugated steroids, and to bile acid production.

    “AKR1 enzymes play important roles in metabolism of androgens, estrogens, progesterone, glucococorticoids, neurosteroids, conjugated steroids, and in the biosynthesis of bile acids.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pro133Arg had a 10-fold higher estimated Km and about 2-fold lower Vmax than wild-type enzyme for 7α-hydroxy-cholesten-3-one.

    “The estimated Km value for Pro133Arg was 10-fold higher and Vmax about 2-fold lower as compared to the wild type enzyme for the bile acid precursor, 7α-hydroxy-cholesten-3-one [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Drury JE Mindnich R Penning TM Characterization of disease-related 5β-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency J Biol Chem 2010 32 24529 24537 20522910 PMC2915689 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With the exception of Pro133Arg, the mutations lie in regions conserved among AKR1D1 homologues and do not participate in catalysis, coenzyme binding, or substrate binding.

    “Except Pro133Arg, these mutations reside in domains highly conserved across AKR1D1 homologues and are not involved in catalysis, coenzyme or substrate binding [21, 101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Di Constanzo L Drury JE Penning TM Christianson DW Crystal structure of human liver Δ4–3-ketosteroid 5β-reductase (AKR1D1) and implications for substate binding and catalysis J Biol Chem 2008 283 16830 16839 18407998 PMC2423251 source

      Not checked in the free run.

    • cites [101] Drury JE Mindnich R Penning TM Characterization of disease-related 5β-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency J Biol Chem 2010 32 24529 24537 20522910 PMC2915689 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HEK293 expression of Leu106Phe and Arg261Cys mutants showed lower expression levels, probably due to decreased stability.

    “Expression of the mutated enzymes in HEK293 cells revealed lower expression levels of Leu106Phe, and Arg261Cys probably due to decreased stability”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Drury JE Mindnich R Penning TM Characterization of disease-related 5β-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency J Biol Chem 2010 32 24529 24537 20522910 PMC2915689 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Takahashi et al. functionally characterized 11 nonsynonymous AKR1C2 SNPs known at the time, but later bioinformatics showed only five are real: Phe46Tyr, Val111Ala, Lys179Gln, Lys185Gln, and Arg258Cys.

    “In AKR1C2 Takahashi et al. functionally characterized 11 nonsynonymous SNPs known at the time but later bioinformatics studies showed that only 5 of these represent real SNPs: Phe46Tyr, Vall11Ala, Lys179Gln, Lys185Gln and Arg258Cys [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Musumeci L Arthur JW Cheung FSG Hoque A Lippman S Reichardt JKV Single nucleotide differences (SNDs) in the dbSNP database may lead to errors in genotyping and haplotyping studies Human Mutation 2009 31 67 73 19877174 PMC2797835 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Androsterone is converted to 3α-Diol by AKR1C3, and 3α-Diol is the immediate precursor of 5α-DHT.

    “Androsterone is converted to 3α-Diol by AKR1C3 which is the immediate precursor of 5α-DHT.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Auchus RJ The backdoor pathway to dihydrotestosterone Trends Endocrinol Metab 2004 15 432 438 15519890 source

      Not checked in the free run.

    • cites [102] Auchus RJ Non-traditional metabolic pathways of adrenal steroids Rev Endocr Metab Disord 2009 10 27 32 18720009 source

      Not checked in the free run.

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

    Interpretationreasoning

    Different expression ratios of AKR1 enzymes may plausibly adjust ligand availability for nuclear and membrane receptors.

    “It is likely that different ratios of AKR1 enzyme expression may tune ligand availability for nuclear and membrane bound receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The mutants showed lower 5β-reductase activity than wild type, in agreement with clinical observations of bile acid deficiency.

    “The mutants thus showed lower 5β-reductase activity as compared to wild type which is in agreement with clinical observations of bile acid deficiency [98, 101].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98] Mindnich R Drury JE Penning TM The effects of disease associated point mutation on 5b-reductase (AKR1D1) enzyme function Chem Biol Interact 2011 191 250 254 21185810 PMC3101292 source

      Not checked in the free run.

    • cites [101] Drury JE Mindnich R Penning TM Characterization of disease-related 5β-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency J Biol Chem 2010 32 24529 24537 20522910 PMC2915689 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SNPs in AKR1C1, AKR1C2, and AKR1C4 have been studied at the protein level, and Phe46Tyr has been associated with disease.

    “So far SNPs in AKR1C1, AKR1C2 and AKR1C4 have been studied at the protein level and Phe46Tyr has been associated with disease [95–97, 99, 103, 104].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [95] Lemonde HA Custard EJ Bouquet J Duran M Overmars H Scambler PJ Mutations in SRD5B1 (AKR1D1, the gene encoding Δ4–3-oxosteroid 5β-reductase, in hepatitis and liver failure in infancy Gut 2003 52 1494 1499 12970144 PMC1773813 source

      Not checked in the free run.

    • cites [96] Gonzales E Cresteil D Baussan C Dabadie A Gerhardt MF Jacquemin E SRBD5B1 (AKR1D1) gene analysis in Δ(4)-3-oxosteroid 5β-reductase deficiency: evidence for primary genetic defect J Hepatol 2004 40 716 718 15030995 source

      Not checked in the free run.

    • cites [97] Ueki I Kimura A Chen HL Yorifuji T Mori J Itoh S SRD5B1 gene analysis needed for the accurate diagnosis of primary 3-oxo-Δ4-steroid 5β-reductase deficiency J Gastroenterology and Hepatology 2009 24 776 785 19175828 source

      Not checked in the free run.

    • cites [99] Seki Y Mizuochi T Kimura A Takahashi T Ohtake A Hayashi SI Two neonatal cholestasis patients with mutations in the SRD5B1 (AKR1D1) gene: diagnosis and bile acid profiles during chenodeoxycholic acid treatment J Inherit Metab Dis 2013 36 565 73 23160874 source

      Not checked in the free run.

    • cites [103] Flueck C Meyer Boeni M Pandey AV Kempna P Miller WL Schoenle EJ Why boys will be boys: Two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation Am J Hum Genetics 2011 89 201 218 21802064 PMC3155178 source

      Not checked in the free run.

    • cites [104] Musumeci L Arthur JW Cheung FSG Hoque A Lippman S Reichardt JKV Single nucleotide differences (SNDs) in the dbSNP database may lead to errors in genotyping and haplotyping studies Human Mutation 2009 31 67 73 19877174 PMC2797835 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the second family, recombination between AKR1C1 and AKR1C3 was detected and a missense AKR1C2 mutation His222Gln was identified.

    “In the second family recombination between AKR1C1 and AKR1C3 was detected and a missense AKR1C2 mutation His222Gln was identified.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Flueck C Meyer Boeni M Pandey AV Kempna P Miller WL Schoenle EJ Why boys will be boys: Two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation Am J Hum Genetics 2011 89 201 218 21802064 PMC3155178 source

      Not checked in the free run.

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

    Premisenone given

    A large number of synonymous and nonsynonymous SNPs have been identified in AKR1 genes.

    “A large number of synonymous and nonsynonymous single nucleotide polymorphisms (SNPs) have been identified in AKR1 genes (Table 5).”
    Quote in the paperNot a substantial claim
76 of 76

  • The paper relies on this without support.

    Phase I and phase II enzymes act sequentially in steroid metabolism.

    “It is generally accepted that phase I and phase II enzymes act sequentially.”

  • The authors state this as an assumption.

    Many synthetic steroids contain a Δ4 or 3-keto,20-keto structural motif and are substrates for AKR1 enzymes.

    “Many synthetic steroids contain the Δ4 or 3-keto, 20-keto-steroid structural motif and are anticipated to be substrates for the AKR1 enzymes.”

  • The paper relies on this without support.

    In estrogen-sensitive tissues, ERα occupancy is proproliferative and ERβ occupancy is antiproliferative.

    “occupancy of ERα is thought to be proproliferative and occupancy of ERβ is thought to be antiproliferative”

  • The paper relies on this without support.

    AKR1C genes are present in the ectopic endometrium of women with endometriosis.

    “AKR1C genes are also expressed in ectopic endometrium of endometriosis patients.”

  • The paper relies on this without support.

    Normal male fetal sexual differentiation depends on synthesis of 5α-DHT for development of male external genitalia.

    “Proper sexual development in male fetus requires synthesis of 5α-DHT which is crucial for differentiation of male external genitalia.”

  • The paper relies on this without support.

    SNP databases can be incomplete and contain inaccuracies.

    “However, SNP databases are not always complete and accurate.”

  • The paper relies on this without support.

    AKR1C enzymes metabolize synthetic steroids used in oral contraceptives, hormone replacement therapy, and steroid anti-inflammatory drugs.

    “Synthetic steroids found in oral contraceptives, hormone replacement therapies and steroid anti-inflammatory drugs are metabolized by AKR1C enzymes.”

  • The paper relies on this without support.

    AKR1C enzymes convert the prodrug tibolone into its active metabolites.

    “For instance; the prodrug tibolone is metabolized by AKR1C enzymes to active compounds”

  • The paper relies on this without support.

    Inhaled corticosteroids act as inhibitors of AKR1D1 and AKR1C4.

    “inhaled corticosteroids inhibit AKR1D1 and AKR1C4”

  • The paper relies on this without support.

    Dydrogesterone and the glucocorticoid budesonide inhibit AKR1 enzymes.

    “Other synthetic steroids, e.g. dydrogesterone, and the glucocorticoids budesonide inhibit AKR1 enzymes”

  • The paper relies on this without support.

    Androgen deprivation increases AKR1C gene expression in prostate cancer.

    “AKR1C genes are up-regulated by androgen deprivation in prostate cancer”
11 of 11

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.

  • AKR1C2 mutation is given two different identities

    Minor

    The mutation list names His906Glu, whereas the subsequent account of the mutants tested names His90Gln.

  • Arg SNP position changes from 258 to 285

    Minor

    The AKR1C2 SNP list names Arg258Cys; the subsequent discussion of the other AKR1C1/2 SNPs instead names Arg285Cys.

  • Lys185 SNP is reported as both Gln and Glu

    Minor

    The list of real AKR1C2 SNPs names Lys185Gln, but the following sentence calls Lys185Glu a SNP in the same characterization.

  • Abstract names the wrong gene in sexual development dysgenesis

    Minor

    The abstract attributes the condition to mutations in AKR1C1 and AKR1C4, but the inherited-mutations section identifies AKR1C2 and AKR1C4 in the affected families.

4 of 4

Cites

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Authors
Rižner, T. L., & Penning, T. M.
Affiliations
  • University of Ljubljana (SI)
  • University of Pennsylvania (US)
Corresponding author
  • Rižner, Tea Lanišnik
  • Penning, Trevor M.
ORCID
Venue
Steroids
Publisher
Elsevier BV
Published
2014-01
Volume
79
Pages
49-63
ISSN
0039-128X (ISSN-L)
DOI
10.1016/j.steroids.2013.10.012
PMC
PMC3870468
OpenAlex
W1978348589
Semantic Scholar
e1e219e4bb0dc810a31e16e01bc8d64b950b9830
Cited by
217
References
108
Citations by year
2026: 20 · 2025: 14 · 2024: 20 · 2023: 19 · 2022: 21 · 2021: 29 · 2020: 16 · 2019: 13 · 2018: 9 · 2017: 17 · 2016: 18 · 2015: 10 · 2014: 10
FWCI
1.42
Type
journal article
Language
en
Open access
Locations
  • Steroids (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Council for International Exchange of Scholars
  • Javna Agencija za Raziskovalno Dejavnost RS
  • National Institutes of Health
  • National Cancer Institute (R01CA090744)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK047015)
  • National Institute of Environmental Health Sciences (P30ES013508)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
AKR1C1, AKR1C2, AKR1C3, AKR1C4, AKR1D1, steroid metabolism, neurosteroids, bile acids, conjugated steroids, nuclear receptor ligand binding, GABAA receptor, NMDA receptor, prostate cancer, breast cancer, endometrial cancer, bile acid deficiency, genetic mutations, single nucleotide polymorphisms
MeSH terms
Bile Acids and Salts, Humans, Mutation, Oxidoreductases, Disorders of Sex Development, Steroids, 20-Hydroxysteroid Dehydrogenases, Receptors, Cytoplasmic and Nuclear

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