Modulation of rat hepatic microsomal monooxygenase enzymes and cytotoxicity by diallyl sulfide

Diallyl sulfide (DAS) and other organosulfur compounds inhibit chemically induced carcinogenic and toxic responses in rodent model systems. A possible mechanism of action is the inhibition of the hepatic cytochrome P450IIE1-dependent bioactivation of the procarcinogens and protoxicants. Previous work showed competitive inhibition by DAS of N-nitrosodimethylamine (NDMA) demethylase activity in vitro, and a reduction in the microsomal level of P450IIE1 after in vivo treatment with DAS. The present studies demonstrated a time- and dose-dependent decrease of hepatic microsomal P450IIE1 activity, induction of P450IIB1 and pentoxyresorufin dealkylase activity, and moderate induction of ethoxyresorufin dealkylase activity by oral DAS treatment. DAS treatment elevated P450IIB1 mRNA but had no effect on P450IIE1 mRNA. Treatment with putative metabolites of DAS, diallyl sulfoxide and diallyl sulfone, led to similar modulations in monooxygenase activities, but the decrease of P450IIE1 activity by the sulfone occurred more rapidly. In studies in vitro, diallyl sulfone caused a metabolism-dependent inactivation of P450IIE1, but such inactivation was not observed with DAS or diallyl sulfoxide. The profile of microsomal testosterone metabolism after DAS treatment indicated an enhancement of P450IIB1-dependent 16β-hydroxylase activity, and a decrease in 6β-hydroxytestosterone production possibly related to a lower level of P450IIIA1 or IIIA2. When rats were subjected to a 48-hr fast and DAS treatment, the starvation-induced microsomal P450IIE1 level was decreased by DAS. Inhibition of hepatotoxicity due to exposure to P450IIE1 substrates, CCl₄ and NDMA, by DAS was observed under a variety of treatment schedules.