Molecular Pharmacology, Vol 5, 174-185, Copyright © 1969 by the American Society for Pharmacology and Experimental Therapeutics

Induction of Drug Metabolism

I. Differences in the Mechanisms by Which Polycyclic Hydrocarbons and Phenobarbital Produce Their Inductive Effects on Microsomal N-Demethylating Systems

¹ Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

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.

Note:
ACKNOWLEDGMENT The authors gratefully acknowledge the able technical assistance of Mrs. Sheila Ham.

This article has been cited by other articles:

				J. E. Gielen and D. W. Nebert Microsomal Hydroxylase Induction in Liver Cell Culture by Phenobarbital, Polycyclic Hydrocarbons, and p,p'-DDT Science, April 9, 1971; 172(3979): 167 - 169. [Abstract] [PDF]