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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: 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.

Authors: Jin, Yi; Mesaros, A Clementina; Blair, Ian A; Penning, Trevor M

Published In Biochem J, (2011 Jul 01)

Abstract: Active sex hormones such as testosterone and progesterone are metabolized to tetrahydrosteroids in the liver to terminate hormone action. One main metabolic pathway, the 5β-pathway, involves 5β-steroid reductase (AKR1D1, where AKR refers to the aldo-keto reductase superfamily), which catalyses the reduction of the 4-ene structure, and ketosteroid reductases (AKR1C1-AKR1C4), which catalyse the subsequent reduction of the 3-oxo group. The activities of the four human AKR1C enzymes on 5β-dihydrotestosterone, 5β-pregnane-3,20-dione and 20α-hydroxy-5β-pregnan-3-one, the intermediate 5β-dihydrosteroids on the 5β-pathway of testosterone and progesterone metabolism, were investigated. Product characterization by liquid chromatography-MS revealed that the reduction of the 3-oxo group of the three steroids predominantly favoured the formation of the corresponding 3α-hydroxy steroids. The stereochemistry was explained by molecular docking. Kinetic properties of the enzymes identified AKR1C4 as the major enzyme responsible for the hepatic formation of 5β-tetrahydrosteroid of testosterone, but indicated differential routes and roles of human AKR1C for the hepatic formation of 5β-tetrahydrosteroids of progesterone. Comparison of the kinetics of the AKR1C1-AKR1C4-catalysed reactions with those of AKR1D1 suggested that the three intermediate 5β-dihydrosteroids derived from testosterone and progesterone are unlikely to accumulate in liver, and that the identities and levels of 5β-reduced metabolites formed in peripheral tissues will be governed by the local expression of AKR1D1 and AKR1C1-AKR1C3.

PubMed ID: 21521174 Exiting the NIEHS site

MeSH Terms: 20-Hydroxysteroid Dehydrogenases/chemistry; 20-Hydroxysteroid Dehydrogenases/metabolism; 3-Hydroxysteroid Dehydrogenases/chemistry; 3-Hydroxysteroid Dehydrogenases/metabolism; Aldo-Keto Reductase Family 1 Member C3; Binding Sites; Catalysis; Humans; Hydroxyprostaglandin Dehydrogenases/chemistry; Hydroxyprostaglandin Dehydrogenases/metabolism; Hydroxysteroid Dehydrogenases/chemistry; Hydroxysteroid Dehydrogenases/metabolism; Ketosteroids/metabolism; Kinetics; Oxidation-Reduction; Oxidoreductases/chemistry; Oxidoreductases/metabolism*; Progesterone/metabolism*; Stereoisomerism; Testosterone/metabolism*

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