美吡拉敏在代谢及与大分子结合方面的种属差异：大鼠、小鼠和仓鼠的比较

Species differences in the metabolism and macromolecular binding of methapyrilene: a comparison of rat, mouse and hamster.

Lampe M A, Kammerer R C

Department of Pharmacology, School of Medicine, University of California, Los Angeles 90024.

Xenobiotica. 1990 Dec;20(12):1269-80. doi: 10.3109/00498259009046626.

Abstract

The metabolism of methapyrilene (MPH) by rat, hamster and mouse liver microsomes in vitro was investigated together with the binding of 14C-MPH to calf thymus DNA after metabolic activation. 2. Both quantitative and qualitative differences in MPH metabolism were observed in these three species. Mouse liver microsomes catalyse the formation of two novel isomers of hydroxypyrdylmethapyrilene (hydroxypyridyl-MPH) as determined by mass spectral analysis. N,N'-Didesmethylmethapyrilene (didesmethyl-MPH) was formed in detectable quantities only when hamster liver microsomes were used. 3. Incubation of liver microsomes from all three species catalysed the binding of 14C-MPH to exogenous DNA, which was quantitatively similar for all three species. The effect of the cytochrome P-450 inhibitor, 2,4-dichloro-6-phenylphenoxyethylamine (DPEA), and methimazole, a flavin-dependent monooxygenase inhibitor, on binding differed significantly for the three species studied.

摘要

研究了大鼠、仓鼠和小鼠肝微粒体在体外对甲吡咯烷（MPH）的代谢，以及代谢活化后14C-MPH与小牛胸腺DNA的结合情况。2. 在这三个物种中观察到了MPH代谢的定量和定性差异。通过质谱分析确定，小鼠肝微粒体催化形成了两种新型羟基吡啶甲吡咯烷（羟基吡啶-MPH）异构体。仅当使用仓鼠肝微粒体时，才形成了可检测量的N，N'-双去甲基甲吡咯烷（双去甲基-MPH）。3. 所有三个物种的肝微粒体孵育均催化14C-MPH与外源DNA的结合，这在所有三个物种中在数量上相似。细胞色素P-450抑制剂2,4-二氯-6-苯氧基乙胺（DPEA）和黄素依赖性单加氧酶抑制剂甲巯咪唑对结合的影响在所研究的三个物种中差异显著。