EFFECTS OF VARIOUS CHEMICAL AGENTS ON DRUG METABOLISM AND CHOLESTEROL BIOSYNTHESIS

The effects of representative inhibitors of drug metabolism, hypocholesterolemic agents and insecticide synergists on microsome-catalyzed drug metabolism and cholesterol biosynthesis were examined in the rat. In the experiments in vitro, both biochemical reactions were inhibited to varying degrees by all of the test compounds. Cholesterol biosynthesis appeared to be more sensitive to these compounds than was the drug metabolism system. However, in an experiment in vivo, only microsome inhibitors prolonged the sleeping time of mice induced by hexobarbital. The administration of AY-9944 and Compound A at doses sufficient to lower the plasma cholesterol level had no effect on the microsomal enzyme activity. Two effects on cholesterol metabolism were observed with microsome inducers. Administration of 3,4-benzpyrene resulted in an elevated plasma cholesterol level in the rat. However, the incorporation of 14C-labeled acetate or mevalonic acid into cholesterol by the liver of benzpyrene-treated rats was not higher than that by the liver of the control rats. Phenobarbital did not elevate the plasma cholesterol level, but the liver from phenobarbital-treated rats showed increased 14C-acetate incorporation into cholesterol. © 1968.