Cytochrome P-450 dependent binding of methapyrilene to DNA in vitro.
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.
D000111:Acetylcysteine / Q000494:pharmacology; D000631:Aminopyridines / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002417:Cattle; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D008701:Methapyrilene / Q000378:metabolism*; D008713:Methimazole / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D012451:Safrole / Q000494:pharmacology
D000631:Aminopyridines; D065607:Cytochrome P-450 Enzyme Inhibitors; C000939:2,4-dichloro-6-phenylphenoxyethylamine; D011285:Pregnenolone Carbonitrile; D009249:NADP; D008713:Methimazole; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D008701:Methapyrilene; D011335:Proadifen; D011078:Polychlorinated Biphenyls; D012451:Safrole; C015959:isosafrole; D000111:Acetylcysteine; D010634:Phenobarbital; D008797:Metyrapone