Molecular Pharmacology, Vol 6, 697-701, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Induction of Drug Metabolism

V. Independent Formation of Cytochromes P-450 and P₁-450 in Rats Treated with Phenobarbital and 3-Methylcholanthrene Simultaneously

¹ Department of Pharmacology, University of Minnesota, College of Medical Sciences, Minneapolis, Minnesota 55455

The administration of 3-methylcholanthrene to rats causes the formation of cytochrome P₁-450, a variant of cytochrome P-450. One concept holds that cytochrome P₁-450 is formed when 3-methylcholanthrene or one of its metabolites combines irreversibly with the type I binding site of previously existing cytochrome P-450. Another concept submits that cytochrome P₁-450 is synthesized independently of cytochrome P-450 and very probably does not contain 3-methylcholanthrene or one of its metabolites. The current study supports the second concept. When phenobarbital, an agent known to induce the synthesis of cytochrome P-450, and 3-methylcholanthrene are administered simultaneously, microsomal levels of cytochrome P-450 hemoprotein, the binding of hexobarbital and aniline to this hemoprotein, and microsomal 3-methyl-4-methylaminoazobenzene N-demethylase activity are elevated nearly to the sums of each of these measurements obtained when the inducing agents are given singly. It was reasoned that if cytochrome P₁-450 results simply from the formation of a stable cytochrome P-450-polycyclic hydrocarbon complex, the P-450 hemoprotein obtained after simultaneous administration of phenobarbital and 3-methylcholanthere should be entirely in the form of cytochrome P₁-450. Studies of the induction of cytochromes P-450 and P₁-450 led to the conclusion that the two hemoproteins are synthesized independently of each other. If 3-methylcholanthrene or one of its metabolites is incorporated into cytochrome P₁-450, the process must occur during the synthesis of new hemoprotein.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the able technical assistance of Dr. Jon Teng and Miss Viola Abbott.