TY - JOUR T1 - Induction of Drug Metabolism JF - Molecular Pharmacology JO - Mol Pharmacol SP - 697 LP - 701 VL - 6 IS - 6 AU - KATHLEEN BIDLEMAN AU - G. J. MANNERING Y1 - 1970/11/01 UR - http://molpharm.aspetjournals.org/content/6/6/697.abstract N2 - 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. ACKNOWLEDGMENTS The authors gratefully acknowledge the able technical assistance of Dr. Jon Teng and Miss Viola Abbott. ER -