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.
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.
authors.affiliation: Department of Pharmacology and Centers of Excellence in Environmental Toxicology and Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: A Clementina
authors.initials: AC
authors.lastname: Mesaros
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001665:Binding Sites; D002384:Catalysis; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000737:chemistry / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000378:metabolism; D007664:Ketosteroids / Q000378:metabolism; D007700:Kinetics; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism*; D013237:Stereoisomerism; D013739:Testosterone / Q000378:metabolism*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D015089:20-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D000074425:Aldo-Keto Reductase Family 1 Member C3; D006911:Hydroxyprostaglandin Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D007664:Ketosteroids; D010088:Oxidoreductases; D011374:Progesterone; D013739:Testosterone; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C487341:AKR1C3 protein, human; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; C021936:3-oxo-5 beta-steroid delta 4-dehydrogenase