The Effect of Allelic Variation in Aldo-Keto Reductase 1C2 on the in Vitro Metabolism of Dihydrotestosterone
Abstract
Aldo-keto reductase (AKR) 1C2 is a human, cytosolic enzyme that has an important role in the deactivation of the potent androgen dihydrotestosterone (DHT). AKR1C2 can regulate the extent and duration of activation of the androgen receptor by catalyzing the reduction of DHT to the less potent receptor ligand 3alpha-diol. In this study, we functionally characterize in vitro the effect of 11 naturally occurring nonsynonymous single nucleotide polymorphisms on the ability of AKR1C2 to reduce DHT to 3alpha-diol. The wild-type and variant enzymes were expressed using a transfected insect cell system, and their kinetic activities were measured using both a specific fluorogenic probe and DHT as substrates. This functional characterization demonstrates that several variant AKR1C2 proteins have significantly reduced or altered reductase activities as shown by their measured kinetic parameters. Data from our two separate in vitro studies revealed significant reductions in V(max) for two variants (F46Y and L172Q) and significantly lower apparent K(m) values for three variants (L172Q, K185E, and R258C) compared with the wild type. These results provide evidence that several naturally occurring nonsynonymous single nucleotide polymorphisms in AKR1C2 result in reduced enzyme activities. These variant AKR1C2 alleles may represent one factor involved in the variable degradation of DHT in vivo.
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The frequency of Phe46Tyr paralleled prostate cancer risk across populations: 15% in individuals of African descent, 5.9% in Europeans, and undetected in Asians.
“The authors observed that the frequency of Phe46Tyr SNP parallelled the risk for prostate cancer in different populations (individuals of African descent 15%, Europeans 5.9%, and undetected in the Asian population).”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [105]
Phe46Tyr had 2.5-fold reduced Vmax compared with wild-type AKR1C2.
“Phe46Tyr had a 2.5-fold reduced enzymatic activity versus wild-type enzyme (Vmax)”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [105]
Lys185Glu and Arg258Cys had significantly lower apparent Km values for reduction of 5α-DHT to 3α-Diol.
“and two SNPs, Lys185Glu and Arg258Cys had significantly lower apparent Km values, when the reduction of 5α-DHT to 3α-Diol was followed [105].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [105]
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- Authors
- Takahashi, R. H., Grigliatti, T. A., Reid, R. E., & Riggs, K. W.
- Affiliations
- University of British Columbia (CA)
- ORCID
- Takahashi, Ryan H.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 329
- Issue
- 3
- Pages
- 1032-1039
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2155920248
- Cited by
- 21
- References
- 39
- Citations by year
- 2024: 3 · 2023: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 3 · 2014: 3 · 2013: 1
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- AKR1C2, dihydrotestosterone, 3alpha-diol, single nucleotide polymorphisms, allelic variation, enzyme kinetics, androgen metabolism, androgen receptor, enzyme activity reduction
- MeSH terms
- Animals, Catalysis, Cell Line, Fluorescent Dyes, Humans, Hydroxysteroid Dehydrogenases, Kinetics, Oxidation-Reduction, Recombinant Proteins, Dihydrotestosterone, Androstane-3,17-diol, Spodoptera, Polymorphism, Single Nucleotide, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
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