Molecular Pharmacology, Vol 15, 410-418, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Hepatic Microsomal Cytochrome P-450-Dependent Monooxygenase Reactions by Fatty Acyl CoA

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

A study was undertaken to determine the mechanism by which fatty acyl CoA (stearoyl or oleoyl CoA) inhibits NADPH-supported hepatic cytochrome P-450-dependent monooxygenase systems. About half of the inhibitory effect of fatty acyl CoA on ethylmorphine N-demethylase activity, and all of the inhibitory effect on aniline p-hydroxylase activity, was shown to be due to stimulation of lipid peroxidation. The remaining half of the inhibition of ethylmorphine demethylation was shown not to be due to a) competition for electrons from NADPH by the fatty acyl CoA desaturase system, b) inhibition of NADPH-cytochrome c reductase or NADPH-cytochrome P-450 reductase, c) 3'5' ADP, which might have been formed from CoA through the action of nucleotide pyrophosphatase, d) a shortage of electrons from NADPH due to an inhibitory effect of fatty acyl CoA on glucose 6-phosphate dehydrogenase, or e) fatty acyl CoA or its products acting as substrate inhibitors. Stearoyl CoA prevented the stimulation of NADPH-cytochrome P-450 reductase by ethylmorphine and caused a small but consistent loss of the type I binding spectrum elicited by ethylmorphine. These observations and the kinetics of the inhibition of ethylmorphine N-demethylase by stearoyl CoA suggest that fatty acyl CoA may inhibit hepatic monooxygenase reactions by acting as a detergent.