NIOSHTIC-2 Publications Search
Metyrapone and other modifiers of microsomal drug metabolism.
Drug Metab Dispos 1973 Jan; 1(1):184-190
The actions of metyrapone (54364) and related compounds on liver microsomal drug metabolizing enzyme systems were reviewed. Metyrapone was a rather specific inhibitor of the 11-beta- hydroxylase of the adrenal cortical mitochondria. Oxidation of several substrates by the somewhat similar cytochrome-P-450 containing system of liver microsomes was inhibited by metyrapone. The oxidation of acetanilide was markedly enhanced when metyrapone was added to the assay system prepared from livers of control and phenobarbital pretreated rats. Metyrapone was reduced to the corresponding secondary alcohol, metyrapol, in liver microsomes. The reduced product was almost as potent an inhibitor of oxidative demethylation as was the parent compound. The chief structural features of the compound were the ketone group and the pair of aromatic nitrogen heterocycles. Acetophenone was able to enhance the rate of hydroxylation of acetanilide in a manner similar to metyrapone. Clofibrate proved to be a very weak inhibitor of drug metabolism. Inhibitory potency toward adrenal steroid 11-beta- hydroxylase equal to or greater than that of metyrapone was demonstrated by two members of the 1-arylimidazole series. For some of the pyridine analogues of acetophenone an enhancement of acetanilide hydroxylation was noted when added to the assay mixture in-vitro. Other of these pyridine analogues caused only inhibition of hydroxylation in the same concentration range. The (1- naphthylvinyl)pyridines caused a prolongation of hexobarbital sleeping time and inhibited hexobarbital metabolism in-vitro. These compounds were fairly potent inhibitors of several drug metabolic pathways.
NIOSH-Grant; NIOSH-Publication; Grants-other; Drug-interaction; Metabolic-study; Liver-microsomal-enzymes; Laboratory-animals; Enzyme-activity
Pharmacology and Therapeutics Univ of Florida Coll of Med Dept of Pharma & Therapeutics Gainesville, Fla 32601
Issue of Publication
Other Occupational Concerns; Grants-other
Drug Metabolism and Disposition
University of Florida Gainesville, Gainesville, Florida
Page last reviewed: September 2, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division