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
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The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3alpha-HSD (AKR1C4), type 2 3alpha(17beta)-HSD (AKR1C3), type 3 3alpha-HSD (AKR1C2) and 20alpha(3alpha)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with k(cat)/K(m) values for substrates that exceeded those obtained with other isoforms by 10-30-fold. In the reduction direction, all isoforms inactivated 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one; 5alpha-DHT) to yield 5alpha-androstane-3alpha,17beta-diol (3alpha-androstanediol). However, only AKR1C3 reduced Delta(4)-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxy-pregn-4-ene-3,20-dione (20alpha-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3alpha-androstanediol to the active hormone 5alpha-DHT. AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione. All isoforms oxidized 17beta-oestradiol to oestrone, and 20alpha-hydroxyprogesterone to progesterone. Discrete tissue distribution of these AKR1C enzymes was observed using isoform-specific reverse transcriptase-PCR. AKR1C4 was virtually liver-specific and its high k(cat)/K(m) allows this enzyme to form 5alpha/5beta-tetrahydrosteroids robustly. AKR1C3 was most prominent in the prostate and mammary glands. The ability of AKR1C3 to interconvert testosterone with Delta(4)-androstene-3,17-dione, but to inactivate 5alpha-DHT, is consistent with this enzyme eliminating active androgens from the prostate. In the mammary gland, AKR1C3 will convert Delta(4)-androstene-3,17-dione to testosterone (a substrate aromatizable to 17beta-oestradiol), oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxyprogesterone, and this concerted reductive activity may yield a pro-oesterogenic state. AKR1C3 is also the dominant form in the uterus and is responsible for the synthesis of 3alpha-androstanediol which has been implicated as a parturition hormone. The major isoforms in the brain, capable of synthesizing anxiolytic steroids, are AKR1C1 and AKR1C2. These studies are in stark contrast with those in rat where only a single AKR with positional- and stereo-specificity for 3alpha-hydroxysteroids exists.
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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”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
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”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
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”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
AKR1C1, AKR1C2 and AKR1C3 catalyze progesterone reduction to 20α-hydroxy-pregn-4-ene-3-one.
“AKR1C1, but also AKR1C2 and AKR1C3 catalyze progesterone reduction to form the less potent progestagen 20α-hydroxy-pregn-4-ene-3-one”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
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).”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
AKR1C enzymes act as 17-ketosteroid reductases to reduce estrone to 17β-estradiol in peripheral tissues.
“AKR1C enzymes also act as 17-ketosteroid reductases to reduce the weak estrogen, estrone to form the potent estrogen, 17β-estradiol in peripheral tissues”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
Other AKR1C enzymes have much lower activities for 17β-estradiol formation.
“Other AKR1C enzymes have much lower activities for 17β-estradiol formation”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
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Mechanisms of Glucocorticoid Action During Development
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Multiple functions of type 10 17β-hydroxysteroid dehydrogenase
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Self-citationOestrogen and progesterone regulation of inflammatory processes in the human endometrium
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Steroid 5α-reductases and 3α-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism
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Self-citationAldo-keto reductase (AKR) 1C3: Role in prostate disease and the development of specific inhibitors
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Self-citationHuman Aldo-Keto Reductases and the Metabolic Activation of Polycyclic Aromatic Hydrocarbons
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Self-citationInhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer
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Self-citationDay, J. M., Tutill, H. J., Purohit, A., & Reed, M. J. (2008) · Endocrine Related Cancer · doi:10.1677/erc-08-0042 · Cited by 123 · see citing works
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Adrenal Androgens and Androgen Precursors-Definition, Synthesis, Regulation and Physiologic Actions
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Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes
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Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action
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Self-citationOverview of AKR1C3: Inhibitor Achievements and Disease Insights
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Disturbed estrogen and progesterone action in ovarian endometriosis
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Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review
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Metabolism and transfer of the mycotoxin zearalenone in human intestinal Caco-2 cells
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Estrogen and Progesterone Metabolism in the Cervix during Pregnancy and Parturition
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AKR1B10: A New Diagnostic Marker of Non–Small Cell Lung Carcinoma in Smokers
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- Authors
- PENNING, T. M., BURCZYNSKI, M. E., JEZ, J. M., HUNG, C.-F., LIN, H.-K., MA, H., MOORE, M., PALACKAL, N., & RATNAM, K.
- Affiliations
- University of Pennsylvania (US)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2000-09-26
- Volume
- 351
- Issue
- 1
- Pages
- 67-77
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1221336
- OpenAlex
- W2045040068
- Cited by
- 649
- References
- 38
- Citations by year
- 2026: 21 · 2025: 20 · 2024: 23 · 2023: 15 · 2022: 15 · 2021: 27 · 2020: 19 · 2019: 22 · 2018: 23 · 2017: 18 · 2016: 23 · 2015: 14 · 2014: 47 · 2013: 28 · 2012: 29
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-47015, R01DK047015)
- 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
- 3α-hydroxysteroid dehydrogenase, aldo-keto reductase superfamily, steroid hormone metabolism, dihydrotestosterone, testosterone, estradiol, progesterone, 20alpha-dihydroprogesterone, 3α-androstanediol, enzyme kinetic parameters, substrate specificity
- MeSH terms
- Androgens, Binding Sites, Catalysis, Cloning, Molecular, Estrogens, Female, Humans, Isoenzymes, Ketones, Kinetics, Male, Organ Specificity, Progestins, Recombinant Proteins, RNA, Messenger, Steroids, Substrate Specificity, 3-Hydroxysteroid Dehydrogenases, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
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