Cytochrome P-450-mediated oxidation of 2-hydroxyestrogens to reactive intermediates.
Cytochrome P-450-mediated oxidation of 2-hydroxyestrogens to reactive intermediates.
复制标题
细胞色素 P-450 介导的 2-羟基雌激素氧化为活性中间体。
DOI：
10.1016/0006-291x(76)91024-x
复制
发表时间：
1976
影响因子：
3.1
通讯作者：
H. Sasame
中科院分区：
文献类型：
--
作者：
S. Nelson;J. Mitchell;E. Dybing;H. Sasame
羟基雌激素、2-羟基雌酮和2-羟基-17 α-乙炔基雌激素是一些口服避孕药中天然雌激素和合成雌激素的氧化产物，它们被大鼠肝微粒体转化为与微粒体蛋白不可逆结合的反应性代谢产物。不可逆结合需要微粒体、氧气和NADPH。NADPH可以被黄嘌呤-黄嘌呤氧化酶系统取代，该系统已知会产生超氧阴离子。超氧化物歧化酶基本上抑制了不可逆结合，在含有NADPH的孵育物中抑制了30%，在含有黄嘌呤-黄嘌呤氧化酶系统的孵育物中抑制了98%。用2-羟基丁酸酯进一步研究表明，微粒体细胞色素P-450在NADPH依赖的不可逆结合中是速率限制性的，因为当与N2：O2（9：1）气氛相比时，NADPH-细胞色素c还原酶抗体对结合的抑制率为62%，CO：O2（9：1）气氛中的抑制率为70%。苯巴比妥（一种已知的细胞色素P-450诱导剂）对2-羟基炔雌醇的不可逆结合没有影响，而另一种P-450诱导剂，双烯醇酮-16 α-甲腈，显著增加了不可逆结合。相反，氯化钴，细胞色素P-450的合成抑制剂，降低P-450和不可逆结合。这些结果与雌激素和2-羟基雌激素与微粒体不可逆结合的机制一致，该机制需要细胞色素P-450产生的超氧阴离子氧化儿茶酚核。
Hydroxyestradiol, 2-hydroxyestrone and 2-hydroxy-17α-ethynylestradiol, oxidation products of naturally occurring estrogens and synthetic estrogens in some oral contraceptives were found to be converted by rat liver microsomes to reactive metabolites that become irreversibly bound to microsomal protein. The irreversible binding required microsomes, oxygen and NADPH. The NADPH could be replaced by a xanthine-xanthine oxidase system which is known to generate superoxide anions. The irreversible binding was substantially inhibited by superoxide dismutase, 30% in those incubations containing NADPH and 98% in those incubations containing the xanthine-xanthine oxidase system. Further studies with 2-hydroxyestradiol showed that microsomal cytochrome P-450 was rate limiting in the NADPH-dependent irreversible binding, because the binding was inhibited 62% by an antibody against NADPH-cytochrome c reductase and 70% in an atmosphere of CO: O 2 (9: 1) when compared to an atmosphere of N 2: O 2 (9: 1). Phenobarbital, a known inducer of cytochrome P-450, had no effect on the irreversible binding of 2-hydroxyestradiol, whereas another inducer of P-450, pregnenolone-16α-carbonitrile, markedly increased the irreversible binding. In contrast, cobaltous chloride, an inhibitor of the synthesis of cytochrome P-450, decreased both P-450 and the irreversible binding. These results are consistent with a mechanism for irreversible binding of estrogens and 2-hydroxyestrogens to microsomes that requires oxidation of the catechol nucleus by cytochrome P-450-generated superoxide anion.