Human Cytosolic Hydroxysteroid Dehydrogenases of the Aldo-ketoreductase Superfamily Catalyze Reduction of Conjugated Steroids
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Aldo-ketoreductase 1C (AKR1C) enzymes catalyze the NADPH-dependent reduction of ketosteroids to hydroxysteroids. They are Phase I metabolizing enzymes for natural and synthetic steroid hormones. They convert 5alpha-dihydrotestosterone (Dht, potent androgen) to 3alpha/beta-androstanediols (inactive androgens) and the prodrug tibolone (Tib) to estrogenic 3alpha/beta-hydroxytibolones. Herein we demonstrate for the first time that human AKR1C enzymes (AKR1C1-4) are able to reduce conjugated steroids such as Dht-17beta-glucuronide (DhtG), Dht-17beta-sulfate (DhtS), and Tib-17beta-sulfate (TibS). Product identities were characterized by liquid chromatography-mass spectrometry, and kinetic parameters of the reactions were determined. The product profile of the reduction of each steroid conjugate by the individual AKR1C isoform was similar to that of the corresponding free steroid except for the reduction of DhtG catalyzed by AKR1C2, where a complete inversion in stereochemical preference to 3beta-reduction (with DhtG) from 3alpha-reduction (with Dht and DhtS) was observed. The catalytic efficiency of 3-keto reduction was modestly affected by the presence of a 17-sulfate group but severely impaired by the presence of a 17-glucuronide group for AKR1C1-3 isoforms. AKR1C4, however, showed superior catalytic efficiencies versus the other isoforms, and those were unaffected by steroid conjugation. Our findings provide evidence for alternative pathways of steroid metabolism where the phase I reaction (reduction) occurs after the phase II reaction (conjugation). Specifically, it is indicated that Dht is metabolized to its metabolite 3alpha-androstanediol-17-glucuronide via the previously unrecognized "conjugation pathway" involving the sequential reactions of UGT2B17 and AKR1C4 in liver but via the conventional "reduction pathway" involving the sequential reactions of AKR1C2 and UGT2B15/17 in prostate.
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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”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
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.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
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”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
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.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
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.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
AKR1C1 and AKR1C4 show unchanged stereochemical preference compared with unconjugated 5α-DHT, forming 3β- and 3α-metabolites, respectively.
“AKR1C1 and AKR1C4 thus show unchanged stereochemical preference when compared to the reduction of the unconjugated 5α-DHT, forming 3β- and 3α-metabolites, respectively.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
The stereospecificity of AKR1C2 and AKR1C3 is reversed with 5α-DHT-17β-glucuronide, forming 3β-hydroxy-5α-androstane-17β-glucuronide instead of the 3α product.
“However, the stereospecificity of AKR1C2 and AKR1C3 is reversed with 5α-DHT-17β-glucuronide forming 3β-hydroxy-5α-androstane-17β-glucuronide instead of 3α-hydroxy-5α-androstane-17β-glucuronide”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
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”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [10]
While phase 1 and phase 2 reactions are classically believed to be sequential, more recent studies have shown metabolism of conjugated steroids by phase 1 enzymes.
“While phase 1 and phase 2 reactions are classically believed to be sequential, more recent studies have shown the metabolism of conjugated steroids by phase 1 enzymes [89].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [89]
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- Authors
- Jin, Y., Duan, L., Lee, S. H., Kloosterboer, H. J., Blair, I. A., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Organon (Netherlands) (NL)
- Corresponding author
- Penning, Trevor M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 284
- Issue
- 15
- Pages
- 10013-10022
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2665056
- OpenAlex
- W2065251992
- Cited by
- 50
- References
- 42
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 4
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01 CA 90744, R01CA090744)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK47015, R01DK047015)
- National Institute of Environmental Health Sciences (P30 ES015857)
- 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
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- steroid conjugates, dihydrotestosterone, tibolone, steroid metabolism, UGT2B17, UGT2B15, phase I metabolism, phase II metabolism, androgen metabolism, enzyme kinetic parameters
- MeSH terms
- Binding Sites, Catalysis, Chromatography, Liquid, Cytosol, Hormones, Humans, Hydroxysteroid Dehydrogenases, Kinetics, Liver, Models, Chemical, Molecular Conformation, Mass Spectrometry, Steroids, Crystallography, X-Ray, Protein Isoforms
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