Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: Implications for phase I and phase II steroid hormone metabolism

Yi Jin, Ling Duan, Seon Hwa Lee, Helenius J. Kloosterboer, Ian A. Blair, Trevor M. Penning

研究成果: Article査読

29 被引用数 (Scopus)

抄録

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 5α-dihydrotestosterone (Dht, potent androgen) to 3α/ β-androstanediols (inactive androgens) and the prodrug tibolone (Tib) to estrogenic 3α/β-hydroxytibolones. Herein we demonstrate for the first time that human AKR1C enzymes (AKR1C1-4) are able to reduce conjugated steroids such as Dht-17β-glucuronide (DhtG), Dht-17β-sulfate (DhtS), and Tib-17β-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 3β-reduction (with DhtG) from 3α-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 3α-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.

本文言語English
ページ(範囲)10013-10022
ページ数10
ジャーナルJournal of Biological Chemistry
284
15
DOI
出版ステータスPublished - 2009 4 10
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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