PT - JOURNAL ARTICLE AU - N. E. SLADEK AU - G. J. MANNERING TI - Induction of Drug Metabolism DP - 1969 Mar 01 TA - Molecular Pharmacology PG - 186--199 VI - 5 IP - 2 4099 - http://molpharm.aspetjournals.org/content/5/2/186.short 4100 - http://molpharm.aspetjournals.org/content/5/2/186.full SO - Mol Pharmacol1969 Mar 01; 5 AB - Hepatic microsomes N-demethylate ethylmorphine and 3-methyl-4-methylaminoazobenzene (3-MMAB). The administration of phenobarbital to male rats stimulates the N-demethylation of both compounds; 3-methylcholanthrene and 3,4-benzpyrene stimulate the N-demethylation of 3-MMAB only. Studies designed to explain this difference in the inductive properties of phenobarbital and the polycyclic hydrocarbons led to the conclusion that polycyclic hydrocarbons cause the synthesis of a new N-demethylating system. This conclusion was arrived at through three experimental approaches: (a) by observing a differential inhibitory effect of SKF 525-A (2-diethylaminoethyl 2,2-diphenylvalerate HCl), (b) by studying the two-substrate kinetics of N-demethylation reactions, and (c) by noting changes in the spectral properties of the reduced microsomal hemoprotein in the presence of ethyl isocyanide. In the untreated rat, one enzyme system is responsible for the N-demethylation of both ethylmorphine and 3-MMAB. Phenobarbital causes an increase in this enzyme system. 3-Methylcholanthrene causes the appearance of a second enzyme system which is capable of N-demethylating 3-MMAB, but not ethylmorphine. The difference in these two enzyme systems can be explained by the appearance of a second microsomal hemoprotein when polycyclic hydrocarbons are administered. This new hemoprotein (or hemoprotein-lipid complex) has been designated cytochrome P1-450 to distinguish it from cytochrome P-450. Cytochrome P1-450 appears to be present in addition to cytochrome P-450 rather than in place of it in microsomes from rats treated with polycyclic hydrocarbons. When reduced and reacted with ethyl isocyanide, each of these cytochromes exists in two pH-dependent, interconvertible forms. The existence of very small amounts of cytochrome P1-450 in microsomes from untreated and phenobarbital-treated rats has not been excluded. ACKNOWLEDGMENTS The authors gratefully acknowledge the able technical assistance of Mrs. Sheila Ham, Mrs. Janice Shoeman, and Mr. Don Shoeman.