Glucocorticoids inhibit interconversion of 7-hydroxy and 7-oxo metabolites of dehydroepiandrosterone: a role for 11beta-hydroxysteroid dehydrogenases?
Glucocorticoids inhibit interconversion of 7-hydroxy and 7-oxo metabolites of dehydroepiandrosterone: a role for 11beta-hydroxysteroid dehydrogenases?
复制标题
糖皮质激素抑制脱氢表雄酮 7-羟基和 7-氧代代谢物的相互转化：11β-羟基类固醇脱氢酶的作用？
DOI：
10.1016/s0003-9861(03)00056-0
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发表时间：
2003
影响因子：
3.9
通讯作者：
Prough,RussellA
中科院分区：
文献类型：
--
作者：
Robinzon,Boaz;Michael,KristyK;Ripp,SharonL;Winters,StephenJ;Prough,RussellA
在人、猪和大鼠肝微粒体中观察到细胞色素P450依赖的脱氢表雄酮代谢产物7α-羟基脱氢表雄酮(7α-OH-DHEA)、7β-羟基脱氢雄酮(7β-OH-DHEA)和7-氧代脱氢表雄酮(7-oxo-DHEA)的形成和相互转化。大鼠肝脏线粒体和细胞核也可将脱氢表雄酮转化为7-α-OH-脱氢表雄酮和7-氧代脱氢表雄酮，但转化率较低。大鼠、猪和人肝微粒体及大鼠肝线粒体和细胞核将7-α-OH-DHEA转化为7-oxo-DHEA。此反应可被皮质酮和11β-羟基类固醇脱氢酶(11βHSD)抑制剂Cbx抑制。大鼠肾脏7-α-OH-DHEA转化为7-oxo-DHEA的速率在NAD+高于NADP+，并被皮质酮抑制。在NADPH作用下，7-氧代脱氢表雄酮被大鼠肝微粒体转化为未知的羟化代谢物和低水平的7-α-羟基脱氢表雄酮。相反，猪肝微粒体组分将7-氧代脱氢表雄酮还原为几乎等量的7-α-和7-β-OH-脱氢表雄酮，而人组分主要产生7-β-OH-脱氢表雄酮。脱氢皮质酮可抑制猪肝微体还原为2种异构体，而人微体仅还原为7α-OH-DHEA；CBX可抑制这两种反应。NADPH或NADH对大鼠肾脏7-oxo-DHEA无明显影响。这些结果表明，脱氢表雄酮首先在肝脏中转化为7-α-OH-脱氢表雄酮，然后在肝脏和肾脏中被氧化为7-氧-脱氢表雄酮。在肝脏中，11βHSD1主要催化7-氧代脱氢表雄酮和7-羟基脱氢表雄酮异构体的相互转化，而在肾脏中，11β脱氢酶2(依赖于NAD+)和11β脱氢酶3(依赖于α+)可能催化7-羟基脱氢表雄酮单向氧化为7-氧代脱氢表雄酮。DHEA独特的物种代谢途径及其代谢物的相互转化避免了将动物研究外推到人类。
The cytochrome P450-dependent formation and subsequent interconversion of dehydroepiandrosterone (DHEA) metabolites 7α-hydroxy-DHEA (7α-OH-DHEA), 7β-hydroxy-DHEA (7β-OH-DHEA), and 7-oxo-DHEA was observed in human, pig, and rat liver microsomal fractions. Rat liver mitochondria and nuclei also converted DHEA to 7α-OH-DHEA and 7-oxo-DHEA, but at a lower rate. With NADP+, and less so with NAD+, rat, pig, and human liver microsomes and rat liver mitochondria and nuclei converted 7α-OH-DHEA to 7-oxo-DHEA. This reaction was inhibited by corticosterone and the 11β-hydroxysteroid dehydrogenase (11βHSD) inhibitor carbenoxolone (CBX). The conversion of 7α-OH-DHEA to 7-oxo-DHEA by rat kidney occurred at higher rates with NAD+than with NADP+and was inhibited by corticosterone. With NADPH, 7-oxo-DHEA was converted to unidentified hydroxylated metabolites and low levels of 7α-OH-DHEA by rat liver microsomes. In contrast, pig liver microsomal fractions reduced 7-oxo-DHEA to nearly equal amounts of 7α- and 7β-OH-DHEA, while human fractions produced mainly 7β-OH-DHEA. Dehydrocorticosterone inhibited the reduction to both isomers by pig liver microsomes, but only to 7α-OH-DHEA by human microsomes; CBX inhibited both reactions. Rat kidney did not reduce 7-oxo-DHEA with either NADPH or NADH. These results demonstrate that DHEA is first converted in liver to 7α-OH-DHEA, which is subsequently oxidized to 7-oxo-DHEA in both liver and kidney. In liver, interconversion of 7-oxo-DHEA and 7-OH-DHEA isomers is largely catalyzed by 11βHSD1, while in kidney 11βHSD2 (NAD+-dependent) and 11βHSD3 (NADP+-dependent) likely catalyze the unidirectional oxidation of 7α-hydroxy-DHEA to 7-oxo-DHEA. Distinct species-specific routes of metabolism of DHEA and the interconversion of its metabolites obviate extrapolation of animal studies to humans.