isosafrole and 2-4-dichloro-6-phenylphenoxyethylamine

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.

Topics: Acetylcysteine; Aminopyridines; Animals; Biotransformation; Cattle; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; DNA; Methapyrilene; Methimazole; Metyrapone; Microsomes, Liver; NADP; Phenobarbital; Polychlorinated Biphenyls; Pregnenolone Carbonitrile; Proadifen; Rats; Safrole