TY - JOUR T1 - THE RATE OF PENTOBARBITAL AND ACETANILIDE METABOLISM BY LIVER MICROSOMES: A FUNCTION OF LIPID PEROXIDATION AND DEGRADATION OF CYTOCHROME P-450 HEME JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 766 LP - 774 VL - 1 IS - 6 AU - M. JACOBSON AU - W. LEVIN AU - A. Y. H. LU AU - A. H. CONNEY AU - R. KUNTZMAN Y1 - 1973/11/01 UR - http://dmd.aspetjournals.org/content/1/6/766.abstract N2 - The time course of oxidative metabolism of pentobarbital and acetanilide by rat liver microsomes is linear for relatively short periods of time. This early deviation from linearity is accompanied by a high rate of NADPH-dependent lipid peroxidation and breakdown of the heme of cytochrome P-450, the terminal oxidase for the microsomal metabolism of foreign compounds, steroids, and fatty acids. The addition of EDTA to the incubation mixture prevents both lipid peroxidation and the decrease in cytochrome P-450 levels, and extends the linearity of pentobarbital and acetanilide metabolism. In contrast, chlorcyclizine, a substrate which blocks lipid peroxidation, is N-demethylated at a constant rate for at least 30 min. Furthermore, a constant rate of pentobarbital metabolism is observed for a prolonged period in the absence of EDTA when rabbit liver microsomes are used. This correlates with the absence of any appreciable lipid peroxidation and hemoprotein breakdown by NADPH in rabbit liver microsomes. The use of EDTA in incubations of rat liver microsomes therefore allows one to increase the sensitivity of existing methods for measuring metabolism of certain substrates which do not prevent lipid peroxidation and the concomitant destruction of cytochrome P-450. Copyright © 1973 by The American Society for Pharmacology and Experimental Therapeutics ER -