Effects of Protein-Calorie Malnutrition on Drug Metabolism in Rat Liver Microsomes

Abstract

The effect of protein-calorie malnutrition in young male rats on the liver microsomal cytochrome P-450 enzyme system functional in the oxidative metabolism of many drugs and endogenous substrates was studied. With liver microsomes from rats fed a low protein diet, in vitro drug metabolism (ethylmorphine N-demethylation) was markedly reduced. Upon addition of hexobarbital, a Type I substrate, hepatic microsomes from these animals showed a much less intense spectral change than microsomes from well-fed age controls. The concentration of cytochrome P-450 was reduced while cytochrome b₅ concentration, NADPH-cytochrome c reductase activity and NADPH-cytochrome P-450 reductase activity were well maintained. Administration of phenobarbital, a known inducer of the hepatic cytochrome P-450 system, increased cytochrome P-450 content, NADPH-cytochrome c reductase activity, NADPH-cytochrome P-450 reductase activity, oxidative drug metabolism, and increased the magnitude of the Type I spectral change. The findings suggest that there is reduced binding of substrates to cytochrome P-450 which precedes enzymic oxidation accounting for the reduced in vitro drug metabolism in microsomes from rats fed low protein diets. Possible explanations for the effect of protein deficiency on substrate binding are discussed.