Cytochrome P-450 dependent binding of methapyrilene to DNA in vitro.
Cytochrome P-450 dependent binding of methapyrilene to DNA in vitro.
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DOI：
10.1093/carcin/8.10.1525
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发表时间：
1987-10
期刊：
影响因子：
4.7
通讯作者：
M. Lampe;R. Kammerer
中科院分区：
文献类型：
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作者：
M. Lampe;R. Kammerer
发现仅在大鼠肝微粒体和NADPH激活后，Methapyrilene（[14 C]MPH）才能与小牛胸腺DNA结合。细胞色素P-450抑制剂2，4-二氯-6-苯基苯氧基乙胺，2-二乙基氨基乙基-2，2-二苯基戊酸酯和甲吡酮抑制结合，但甲巯咪唑，黄素依赖性单加氧酶抑制剂，没有影响。然而，1，2-环氧-3，3，3-三氯丙烷，一种环氧化物水解酶抑制剂，减少结合30%。用异黄樟油素、双烯醇酮-16 α-腈或苯巴比妥预处理大鼠对结合几乎没有影响，而3-甲基胆蒽预处理使结合降低37%。无论是N-乙酰半胱氨酸，谷胱甘肽，过氧化氢酶或谷胱甘肽过氧化物酶的存在下孵育减少结合DNA，而超氧化物歧化酶没有影响。这些数据表明，MPH被代谢激活的物种结合到DNA，这种激活可能是介导的细胞色素P-450同工酶。
Methapyrilene ([14C]MPH) was found to bind to calf thymus DNA only after activation by both rat liver microsomes and NADPH. The cytochrome P-450 inhibitors 2,4-dichloro-6-phenylphenoxyethylamine, 2-diethylaminoethyl-2,2-diphenylvalerate and metyrapone inhibited binding, but methimazole, a flavin-dependent monooxygenase inhibitor, had no effect. However, 1,2-epoxy-3,3,3-trichloropropane, an epoxide hydrolase inhibitor, decreased binding by 30%. Pre-treatment of rats with isosafrole, pregnenolone-16 alpha-carbonitrile or phenobarbital had little or no effect on binding while 3-methylcholanthrene pretreatment decreased binding by 37%. Incubations in the presence of either N-acetylcysteine, glutathione, catalase or glutathione-peroxidase decreased binding to DNA while superoxide dismutase had no effect. These data suggest that MPH is metabolically activated to a species which binds to DNA and that this activation may be mediated by cytochrome P-450 isozymes.