Molecular Pharmacology, Vol 5, 1-9, Copyright © 1969 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Metyrapone on liver Microsomal Drug Oxidations

¹ Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida 32601

Metyrapone [2-methyl-1,2-bis(3-pyridyl)-1-propanone], an inhibitor of adrenal steroid hydroxylation, has been shown to affect a number of liver microsomal drug-oxidizing enzyme systems. The metabolism of hexobarbital and that of aminopyrine are inhibited in vitro by this drug in microsomal preparations from control and phenobarbital-treated rats. Hexobarbital sleeping time is prolonged by metyrapone in both groups of rats. Demethylation of morphine and hydroxylation of tyramine are inhibited to a lesser extent, and NADPH oxidase is little affected. In contrast, the effect of metyrapone on the formation of phenolic metabolites from acetanilide follows a biphasic relationship with respect to metyrapone concentration: inhibition occurs only at very high concentrations, and the reaction is greatly enhanced at lower concentrations with both control and phenobarbital-induced preparations. Trichloroethylene oxidation is also enhanced by metyrapone in both preparations, but the enhancement in phenobarbital-induced preparations is superimposed on an inhibitory effect. Studies with the latter pathway show that both effects are independent of the NADPH-generating system, and are exerted in a reversible manner.

Note:
ACKNOWLEDGMENTS I thank Dr. J. J. Chart of the Ciba Pharmaceutical Company for generous supplies of metyrapone, Dr. A. H. Anton and Mr. D. F. Sayre for performing the determinations of dopamine, Dr. Betty Vogh for some of the data of Fig. 4, and Miss Elsa Ortiz for her excellent technical assistance.

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