Induction of drug metabolism. I. Differences in the mechanisms by which polycyclic hydrocarbons and phenobarbital produce their inductive effects on microsomal N-demethylating systems.

The administration of 3,4-benzpyrene, 3-methylcholanthrene, or phenobarbital to male rats stimulated the N-demethylation of 3-methyl-4-methylaminoazobenzene (3-MMAB) by hepatic microsomes, but only phenobarbital stimulated the N-demethylation of ethylmorphine. Simultaneous administration of maximum stimulatory doses of 3-methylcholanthrene and phenobarbital resulted in additive stimulation of N-demethylation of 3-MMAB, whereas similar treatment with 3,4-benzpyrene and 3-methylcholanthrene did not stimulate 3-MMAB N-demethylation beyond that observed when either was administered singly. Thioacetamide prevented increases in N-demethylation resulting from phenobarbital administration, but had little effect on increased drug metabolism resulting from 3-methylcholanthrene administration. It was concluded that 3,4-benzpyrene and 3-methylcholanthrene stimulate hepatic microsomal drug-metabolizing activity by the same mechanism and that phenobarbital stimulates drug metabolism through a different mechanism. During phenobarbital administration parallel increases were observed in the N-demethylase activities and in the cytochrome P-450 content of microsomes; when phenobarbital was discontinued, microsomal N-demethylase activities and cytochrome P-450 content decreased in a parallel manner. Thioacetamide, administered alone, caused concomitant decreases in N-demethylase activities and cytochrome P-450 content. When given with phenobarbital, thioacetamide prevented the usual increases in N-demethylase activities and in cytochrome P-450 content seen when phenobarbital is administered. Polycyclic hydrocarbons caused an increase in microsomal P-450 content and in 3-MMAB N-demethylase activity, but the increases were not parallel. No increase in ethylmorphine N-demethylase activity occurred even though the content of microsomal hemoprotein was elevated. These studies suggested either that cytochrome P-450 is not rate-limiting in the over-all ethylmorphine N-demethylation reaction or that the administration of polycyclic hydrocarbons causes the synthesis of a microsomal hemoprotein different from that which was present initially in that it is capable of participating in the N-demethylation of 3-MMAB, but not of ethylmorphine.