Induction of cytochromes P450IIE1 and P450IIB1 by secondary ketones and the role of P450IIE1 in chloroform metabolism.
Induction of cytochromes P450IIE1 and P450IIB1 by secondary ketones and the role of P450IIE1 in chloroform metabolism.
复制标题
仲酮对细胞色素 P450IIE1 和 P450IIB1 的诱导以及 P450IIE1 在氯仿代谢中的作用。
DOI：
10.1016/0041-008x(89)90320-7
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发表时间：
1989
影响因子：
3.8
通讯作者：
Yang,CS
中科院分区：
文献类型：
--
作者：
Brady,JF;Li,D;Ishizaki,H;Lee,M;Ning,SM;Xiao,F;Yang,CS
已有研究表明，线性仲酮对氯仿肝毒性的增强作用随着碳链长度的增加而增加。本工作探讨了这种增强是由于P450IIE1诱导的可能性。用顶空气相色谱检测，丙酮处理的大鼠在微粒体存在的情况下，氯仿的新陈代谢比对照组提高了三倍。加入抗P450IIE1的单抗可抑制81%的代谢。P450IIE1的替代底物也具有抑制作用。用纯化、重组的P450IIE1和细胞色素b5观察到氯仿代谢，但用P450IIB1没有检测到。本文研究了三种次生酮对大鼠肝微粒体细胞色素P450、P450IIE1和P450IIB1两种同工酶的诱导作用。丙酮、≤、2-丁酮和2-己酮的氧化速率和免疫反应蛋白水平均随丙酮、2-丁酮和2-己酮的增加而增加。这些结果为P450IIE1的诱导在增强现象中的作用提供了进一步的证据。
It has been shown previously that the potentiation of chloroform-induced hepatotoxicity by linear secondary ketones increases with the carbon-chain length. The present work examines the possibility that this potentiation is due to the induction of P450IIE1. The metabolism of chloroform, as measured using headspace gas chromatography, in the presence of microsomes from acetone-treated rats was elevated threefold compared to controls. Inclusion of monoclonal antibody against P450IIE1 inhibited the metabolism by 81%. Alternate substrates of P450IIE1 were also inhibitory. Chloroform metabolism was observed using purified, reconstituted P450IIE1 plus cytochrome b5, but was not detected using P450IIB1. The inductive effect of 18-hr oral pretreatment (15 mmol/kg body wt) with each of three secondary ketones on two isozymes of rat liver microsomal cytochrome P450, P450IIE1, and P450IIB1 was studied. The content of total microsomal P450 and NADPH-dependent cytochrome c reductase, the rates of oxidation of N-nitrosodimethylamine, benzphetamine, and pentoxyresorufin, as well as levels of immunoreactive protein for both of the isozymes were elevated by the pretreatments in the rank order of acetone ≤ 2-butanone < 2-hexanone, in agreement with other trends noted by previous investigators. The results provide further evidence for the role of P450IIE1 induction in the potentiation phenomenon.