Elsevier

Steroids

Volume 79, January 2014, Pages 49-63
Steroids

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

https://doi.org/10.1016/j.steroids.2013.10.012Get rights and content

Highlights

  • The aldo–keto reductase superfamily contains five human steroid-metabolizing enzymes.

  • AKR1C isoforms act as 3-, 17- and 20-ketosteroid reductases.

  • AKR1D1 is the sole steroid 5β-reductase in humans.

  • AKR enzymes control ligand access to nuclear and membrane bound receptors.

  • Expression profiles, inherited mutations and SNP support their roles in human disease.

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 Δ4-3-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.

Section snippets

Enzymes of steroid metabolism

Imbalance in the biosynthesis and inactivation of steroids can lead to development of disease, including hormonally dependent cancer, of the breast, prostate, endometrium and ovary [1], and to diseases such as benign prostatic hyperplasia, endometriosis, cholestasis, neonatal liver failure, neurological disorders [2], [3], [4], [5], [6] and malformation or differentiation of the genitalia [7]. The metabolism of steroids involves phase I and phase II enzymes and has an important role in human

Human AKR1 enzymes implicated in steroid metabolism

Human AKR1 enzymes implicated in steroid metabolism are members of the AKR1C and AKR1D subfamilies. 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 [14], Fig. 1. These enzymes are expressed in different tissues, while AKR1C4 is mainly liver specific [14]. AKR1C enzymes share a high percentage of

AKR1 enzymes control concentrations of receptor ligands

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. These receptors bind to DNA response elements as homo or heterodimers, recruit co-activators or co-repressors and thus regulate gene transcription [4], [14], [47]. Additionally,

Expression of human AKR1 genes in disease

As AKR1 enzymes play pivotal roles in regulating steroid levels changes in gene expression are anticipated to play roles in disease pathogenesis. The AKR1C1AKR1C4 genes are located on chromosome 10p15-p14, and the AKR1D1 gene is located on chromosome 7q32-q33. AKR1C1AKR1C4 genes comprise 12 exons and AKR1D1 has 9 exons. Three alternatively spliced protein encoding mRNA variants were predicted for AKR1C2, AKR1C3 and AKR1D1 genes in the NCBI database (Table 5). AKR1C2 transcript variants 1 and

Genetics of human AKR1 enzymes

Inherited or SNP allelic variants in AKR1 genes may affect the metabolism of exogenous and endogenous steroids and may also contribute to the development of pathophysiological processes.

Future directions

AKR1 enzymes play important roles in metabolism of androgens, estrogens, progesterone, glucococorticoids, neurosteroids, conjugated steroids, and in the biosynthesis of bile acids. Although AKR1 activities towards representative substrates from these steroid classes have been studied the list is far from comprehensive. A more complete understanding of substrate specificities of AKR1 enzymes and the products they generate may reveal additional physiological and/or pathophysiological roles for

Acknowledgements

This work was supported by grants 1R01-DK47015, 1R01-CA90744 and P30-ES013508 to T.M.P. from the National Institutes of Health, J3-4135 and SLO-USA grants from Slovenian Research Agency, and a Fulbright Grant from Council of International Exchange of Scholars to T.L.R.

References (108)

  • R.B. Iyer et al.

    Human hepatic cortisol reductase activities: enzymatic properties and substrate specificities of cytosolic cortisol Δ4-5β-reductase and dihydrocortisol-3-α-oxidoreductase(s)

    Steroids

    (1990)
  • W.C. Cooper et al.

    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)
  • K.K. Sharma et al.

    Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid target tissues

    Mol Cell Endocrinol

    (2006)
  • M.C. Byrns et al.

    An indomethacin analogue, N-(4-chlorobenzoyl) melatonin, is a selective inhibitor of aldo–keto reductase 1C3 (type 2 3α-HSD, type 5 17β-HSD, and prostaglandin F synthase) a potential target for the treatment of hormone dependent and independent malignancies

    Biochem Pharmacol

    (2008)
  • M.C. Byrns et al.

    Overexpression of aldo–keto reductase 1C3 (AKR1C3) in LNCaP cells diverts androgen metabolism towards testosterone resulting in resistance to the 5α-reductase inhibitor finasteride

    J Steroid Biochem Mol Biol

    (2012)
  • R.J. Auchus

    The backdoor pathway to dihydrotestosterone

    Trends Endocrinol Metab

    (2004)
  • Y. Higaki et al.

    Selective and potent inhibitors of human 20α-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone

    Chem Biol Interact

    (2003)
  • N. Sharifi et al.

    Steroid biosynthesis and prostate cancer

    Steroids

    (2012)
  • M.C. Byrns et al.

    Aldo–keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer

    J Steroid Biochem Mol Biol

    (2010)
  • A.M. Traish

    5α-Reductases in human physiology: an unfolding story

    Endocr Pract

    (2012)
  • M.-L. Lu et al.

    Purification, reconstitution, and steady-state kinetics of the trans-membrane 17β-hydroxysteroid dehydrogenase 2

    J Biol Chem

    (2002)
  • L. Wu et al.

    Expression cloning and characterization of human 17β-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 α-hydroxysteroid dehydrogenase activity

    J Biol Chem

    (1993)
  • S.A. Lee et al.

    Retinol dehydrogenase 10 but not retinol/sterol dehydrogenase(s) regulates the expression of retinoic acid-responsive genes in human transgenic skin raft culture

    J Biol Chem

    (2011)
  • L.B. Moore et al.

    Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands

    J Biol Chem

    (2000)
  • O.A. Barski et al.

    Alternative splicing in the aldo–keto reductase superfamily: implications for protein nomenclature

    Chem-Biol Interact

    (2013)
  • B.S. Taylor et al.

    Integrative genomic profiling of human prostate cancer

    Cancer Cell

    (2010)
  • T.M. Downs et al.

    PTHrP stimulates prostate cancer cell growth and upregulates aldo–keto reductase 1C3

    Cancer Lett

    (2011)
  • B. Han et al.

    Expression of 17β-hydroxysteroid dehydrogenase type 2 and type 5 in breast cancer and adjacent non-malignant tissue: a correlation to clinicopathological parameters

    J Steroid Biochem Mol Biol

    (2008)
  • H. Sasano et al.

    Intracrinology of estrogens and androgens in breast carcinoma

    J Steroid Biochem Mol Biol

    (2008)
  • T. Šmuc et al.

    Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer

    Mol Cell Endocrinol

    (2009)
  • M. Sinreih et al.

    Altered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer

    Chem Biol Interact

    (2013)
  • K. Ito et al.

    17β-hydroxysteroid dehydrogenases in human endometrium and its disorders

    Mol Cell Endocrinol

    (2006)
  • N. Hevir et al.

    Aldo–keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis

    Chem Biol Interact

    (2011)
  • E. Gonzales et al.

    SRBD5B1 (AKR1D1) gene analysis in Δ(4)-3-oxosteroid 5β-reductase deficiency: evidence for primary genetic defect

    J Hepatol

    (2004)
  • R. Mindnich et al.

    The effects of disease associated point mutation on 5β-reductase (AKR1D1) enzyme function

    Chem Biol Interact

    (2011)
  • B.E. Henderson et al.

    Hormonal carcinogenesis

    Carcinogenesis

    (2000)
  • T.M. van der Sluis et al.

    Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer

    BJU Int

    (2012)
  • T. Lanišnik Rižner

    Estrogen metabolism and action in endometriosis

    Mol Cell Endocrinol

    (2009)
  • S.S. Sundaram et al.

    Mechanisms of disease: inborn errors of bile acid synthesis

    Nat Clin Pract Gastroenterol Hepatol

    (2008)
  • M.C. Hardoy et al.

    Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder

    J Clin Psychopharmacol

    (2006)
  • W.L. Miller et al.

    The molecular biology, biochemistry and physiology of human steroidogenesis and its disorders

    Endocrine Rev

    (2011)
  • M.J. Bennett et al.

    Structure of 3α-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+

    Biochemistry

    (1996)
  • T.M. Penning et al.

    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)
  • T. Lanišnik Rižner et al.

    Human type 3 3α-hydroxysteroid dehydrogenase (aldo–keto reductase 1C2) and androgen metabolism in prostate cells

    Endocrinology

    (2003)
  • T.M. Penning et al.

    Steroid hormone transforming aldo–keto reductases and cancer

    Ann N Y Acad Sci

    (2009)
  • S. Steckelbroeck et al.

    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)
  • D.W. Russel et al.

    Bile acid biosynthesis

    Biochemistry

    (1992)
  • L. Di Constanzo et al.

    Crystal structure of human liver Δ4-3-ketosteroid 5β-reductase (AKR1D1) and implications for substate binding and catalysis

    J Biol Chem

    (2008)
  • J.M. Jez et al.

    Comparative anatomy of the aldo–keto reductase superfamily

    Biochem J

    (1997)
  • K.H. Kondo et al.

    Cloning and expression of cDNA of human Δ4-3-oxosteroid 5β-reductase and substrate specificity of the expressed enzyme

    Eur J Biochem

    (1994)
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