Roles of cytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes
Roles of cytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes
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DOI：
10.1021/tx970217f
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发表时间：
1998-06-01
影响因子：
4.1
通讯作者：
Shimada, T
中科院分区：
文献类型：
--
作者：
Yamazaki, H;Shaw, PM;Shimada, T
在检测的7种cDNA表达的人细胞色素P450（P450）酶（P450 1A 2、2B 6、2C 9、2C 19、2D 6、2 E1和3A 4）中，P450 1A 2在催化雌二醇和雌酮的2-和4-羟基化中最具活性。P450 3A 4和P450 2C 9也催化这些反应，尽管程度低于P450 1A 2。P450 1A 2也有效地氧化雌二醇在16 α-位，但在雌酮16 α-羟基化中活性较低;后者反应和雌二醇16 α-羟基化也由P450 3A 4以显著水平催化。抗P450 1A 2抗体抑制这两种雌激素的2-和4-羟基化催化的肝微粒体的一些人样本检查。在人肝微粒体中，抗P450 1A 2和抗P450 3A 4均抑制雌酮16 α-羟基化，而抗P450 3A 4显著抑制雌酮16 α-羟基化。氟伏沙明有效地抑制含有高水平P450 1A 2的人肝脏样品中的雌激素羟基化，而酮康唑影响P450 3A 4水平高的人样品中的这些活性。α-萘啶酮刺激或没有影响肝微粒体催化的雌二醇羟基化;这种影响的强度取决于人体样本及其P450。有趣的是，在抗P450 3A 4抗体的存在下，发现α-萘酚酮能够抑制由人肝微粒体催化的雌二醇和雌酮2-羟基化。结果表明，这两个P450的1A 2和3A 4在氧化雌二醇和雌酮在人类肝脏中的主要作用，这两个P450形式在肝微粒体中的内容确定P450酶是最重要的肝雌激素羟基化由个人。P450 3A 4可能比P450 1A 2在某些雌激素羟基化反应中发挥更重要的作用。了解P450在这些雌激素羟基化中的作用与目前激素致癌作用的争议有关[Service，R. F.（1998）Science 279，1631-1633]。
Of seven cDNA-expressed human cytochrome P450 (P450) enzymes (P450s 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) examined, P450 1A2 was the most active in catalyzing 2- and 4-hydroxylations of estradiol and estrone. P450 3A4 and P450 2C9 also catalyzed these reactions although to lesser extents than P450 1A2. P450 1A2 also efficiently oxidized estradiol at the 16 alpha-position but was less active in estrone 16 alpha-hydroxylation; the latter reaction and also estradiol 16 alpha-hydroxylation were catalyzed by P450 3A4 at significant levels. Anti-P450 1A2 antibodies inhibited 2- and 4-hydroxylations of these two estrogens catalyzed by liver microsomes of some of the human samples examined. Estradiol 16 alpha-hydroxylation was inhibited by both anti-P450 1A2 and anti-P450 3A4, while estrone 16 alpha-hydroxylation was significantly suppressed by anti-P450 3A4 in human liver microsomes. Fluvoxamine efficiently inhibited the estrogen hydroxylations in human liver samples that contained high levels of P450 1A2, while ketoconazole affected these activities in human samples in which P450 3A4 levels were high. alpha-Naphthoflavone either stimulated or had no effect on estradiol hydroxylation catalyzed by liver microsomes; the intensity of this effect depended on the human samples and their P450s. Interestingly, in the presence of anti-P450 3A4 antibodies, cr-naphthoflavone was found to be able to inhibit estradiol and estrone 2-hydroxylations catalyzed by human liver microsomes. The results suggest that both P450s 1A2 and 3A4 have major roles in oxidations of estradiol and estrone in human liver and that the contents of these two P450 forms in liver microsomes determine which P450 enzymes are most important in hepatic estrogen hydroxylation by individual humans. P450 3A4 may be expected to play a more important role for some of the estrogen hydroxylation reactions than P450 1A2. Knowledge of roles of individual P450s in these estrogen hydroxylations has relevance to current controversies in hormonal carcinogenesis [Service, R. F. (1998) Science 279, 1631-1633].