Metabolism of 3-methylindole by porcine liver microsomes: Responsible cytochrome P450 enzymes
Metabolism of 3-methylindole by porcine liver microsomes: Responsible cytochrome P450 enzymes
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DOI：
10.1093/toxsci/55.2.284
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发表时间：
2000-06-01
影响因子：
3.8
通讯作者：
Squires, EJ
中科院分区：
文献类型：
--
作者：
Diaz, GJ;Squires, EJ
采用选择性化学抑制剂研究了不同细胞色素P450酶对3-甲基吲哚（3 MI）代谢的影响。筛选了8种P450酶的化学抑制剂对猪微粒体中3 MI代谢的抑制特异性：α-萘啶酮（CYP 1A 1/2）、8-甲氧基吡喃酮（CYP 2A 6）、薄荷呋喃（CYP 2A 6）、二乙基二硫代氨基甲酸酯（CYP 2A 6）、4-甲基吡唑（CYP 2 E1）、磺胺苯吡唑（CYP 2C 9）、奎尼丁（CYP 2D 6）和醋竹桃霉素（CYP 3A 4）。3 MI代谢产物的产生仅受微粒体孵育物中存在CYP 2A 6和CYP 2 E1抑制剂的影响。在第二项实验中，通过蛋白质免疫印迹分析一组猪微粒体（n = 30）的CYP 2A 6含量及其香豆素7-羟基化活性（CYP 2A 6活性）。CYP 2A 6含量和酶活性与3 MI脂肪含量呈高度负相关。本研究的结果表明，CYP 2A 6猪直系同源物在3 MI的代谢中起着重要的作用，CYP 2A 6水平和/或活性的测量可能是3 MI诱导的公猪腐臭的有用标志物。
The role of different cytochrome P450 enzymes on the metabolism of 3-methylindole (3MI) was investigated using selective chemical inhibitors. Eight chemical inhibitors of P450 enzymes were screened for their inhibitory specificity towards 3MI metabolism in porcine microsomes: alpha-naphthoflavone (CYP1A1/2), 8-methoxypsoralen (CYP2A6), menthofuran (CYP2A6), diethyldithiocarbamate (CYP2A6), 4-methylpyrazole (CYP2E1), sulphaphenazole (CYP2C9), quinidine (CYP2D6), and troleandomycin (CYP3A4). The production of 3MI metabolites was only affected by the presence of inhibitors of CYP2A6 and CYP2E1 in the microsomal incubations. In a second experiment, a set of porcine microsomes (n = 30) was analyzed for CYP2A6 content by protein immunoblot analysis and for their coumarin 7-hydroxylation activity (CYP2A6 activity). Both CYP2A6 content and enzymatic activity were found to be highly and negatively correlated with 3MI fat content. The results of the present study indicate that the CYP2A6 porcine ortholog plays an important role in the metabolism of 3MI and that measurement of CYP2A6 levels and/or activity could be a useful marker for 3MI-induced boar taint.