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.
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Research Article|
June 14 2011
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
Yi Jin
;
Yi Jin
*Department of Pharmacology and Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, U.S.A.
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A. Clementina Mesaros
;
A. Clementina Mesaros
*Department of Pharmacology and Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, U.S.A.
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Ian A. Blair
;
Ian A. Blair
*Department of Pharmacology and Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, U.S.A.
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Trevor M. Penning
Trevor M. Penning
1
*Department of Pharmacology and Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, U.S.A.
1To whom correspondence should be addressed (email penning@upenn.edu).
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Biochem J (2011) 437 (1): 53–61.
Article history
Received:
November 03 2010
Revision Received:
April 20 2011
Accepted:
April 26 2011
Accepted Manuscript online:
April 26 2011
Citation
Yi Jin, A. Clementina Mesaros, Ian A. Blair, Trevor M. Penning; 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. Biochem J 1 July 2011; 437 (1): 53–61. doi: https://doi.org/10.1042/BJ20101804
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