Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes
Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes
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DOI：
10.1006/abbi.1997.0302
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发表时间：
1997-10-01
影响因子：
3.9
通讯作者：
Shimada, T
中科院分区：
文献类型：
--
作者：
Yamazaki, H;Shimada, T
在重组P450酶和人肝微粒体中研究了人细胞色素P450（P450或CYP 19）2C 9、2C 19和3A 4在孕酮和睾酮氧化中的作用。体外抑制实验表明，孕酮及其17 α-和21-羟基化代谢产物和11-脱氧皮质醇抑制CYP 2C 19依赖的R-华法林7-羟基化活性，其中孕酮的活性最强。这些甾体化合物也抑制CYP 2C 19依赖的S-华法林7-羟基化活性，但抑制程度较低。在人肝微粒体中发现Progestrin是CYP 2C 19和CYP 2C 9的竞争性抑制剂。重组CYP 2C 19催化孕酮形成21-羟孕酮作为主要产物，16 α-和17 α-羟孕酮作为次要产物。CYP 2C 9也具有黄体酮21-羟基化活性，尽管活性低于CYP 2C 19催化的活性。测定CYP 2C 19孕酮21-羟基化活性的Vmax/K-m比分别为CYP 2C 9和3A 4的13倍和32倍。CYP 3A 4氧化孕酮形成16 α-、6 β-和2 β-羟孕酮作为主要产物，α-羟孕酮作为次要产物，但不产生可检测水平的17 α-羟孕酮。免疫抑制实验表明，抗CYP 2C 9（抑制CYP 2C 9和CYP 2C 19催化活性）抑制人和猴肝微粒体催化的孕酮21-羟基化活性，抗CYP 2C 11抑制雄性大鼠肝微粒体催化的孕酮21-羟基化活性。CYP 2C 19也被发现在17位氧化睾酮形成雄烯二酮。抗CYP 2C 9和抗CYP 2C 11分别抑制人和猴以及雄性大鼠肝微粒体催化的雄烯二酮形成。这些结果表明，CYP 2C 19在人肝微粒体孕酮和睾酮的氧化中起重要作用，尽管这些代谢途径的生理意义尚不清楚，但CYP 2C 9可能对人肝微粒体孕酮和睾酮的代谢具有一定的催化作用，但程度小于CYP 2C 19。(C)北京：科学出版社.
Roles of human cytochrome P450 (P450 or CYP) 2C9, 2C19, and 3A4 in the oxidation of progesterone and testosterone were studied in recombinant P450 enzymes and in human liver microsomes. In vitro inhibition experiments showed that progesterone and its 17 alpha- and 21-hydroxylated metabolites and 11-deoxycortisol suppressed the CYP2C19-dependent R-warfarin 7-hydroxylation activities, with progesterone being the most active, These steroid chemicals also inhibited CYP2C9-dependent S-warfarin 7-hydroxylation activities though lesser extents seen with those in CYP2C19 enzyme. Progesterone was found to be a competitive inhibitor of CYP2C19 and CYP2C9 in human liver microsomes. Recombinant CYP2C19 catalyzed progesterone to form 21-hydroxyprogesterone as a major product and 16 alpha- and 17 alpha-hydroxyprogesterone as minor products. CYP2C9 also had progesterone 21-hydroxylation activities, although the activities were lower than those catalyzed by CYP2C19. V-max/K-m ratios for the progesterone 21-hydroxylation activity of CYP2C19 were determined to be 13- and 32-fold higher than those of CYP2C9 and 3A4, respectively. CYP3A4 oxidized progesterone to form 16 alpha-, 6 beta-, and 2 beta-hydroxyprogesterone as major products and al-hydroxyprogesterone as a minor product, but did not produce detectable levels of 17 alpha-hydroxyprogesterone. Immunoinhibition experiments suggested that anti-CYP2C9 (which inhibits both CYP2C9 and CYP2C19 catalytic activities) suppressed the progesterone 21-hydroxylation activities catalyzed by liver microsomes of humans and monkeys and that anti-CYP2C11 inhibited the progesterone 21-hydroxylation activities catalyzed by liver microsomes of male rats. CYP2C19 was also found to oxidize testosterone at 17-position to form androstenedione. Androstenedione formation catalyzed by liver microsomes of humans and monkeys and of male rats was suppressed by anti-CYP2C9 and anti-CYP2C11, respectively. These results suggest that CYP2C19 plays important roles in the oxidation of progesterone and testosterone in human liver microsomes, although the physiological significance of these metabolic pathways remains unclear, CYP2C9 may have some, but lesser extent than those by CYP2C19, of the catalytic roles for the metabolism of progesterone and testosterone by human liver microsomes. (C) 1997 Academic Press.