Modification of microsomal membrane components and induction of hepatic drug biotransformation in rats on a high cholesterol diet

The effect of cholesterol on the microsomal membrane components and the induction of drug–metabolizing enzymes was studied in rats after feeding with a two per cent cholesterol diet and administration of phenobarbitone or 3–methylcholanthrene intraperitoneally. The results revealed that cholesterol affected both the amount and the binding properties of protein, phospholipid and cholesterol in microsomes. Cholesterol also modified the effects of phenobarbitone and 3–methylcholanthrene on microsomal membranes. The administration of inducers increased the liver–body weight ratio significantly. Phenobarbitone enhanced NADPH cytochrome c reductase activity in native microsomes by about 2–fold. The aryl hydrocarbon hydroxylase activity was increased markedly by both phenobarbitone and 3–methylcholanthrene. The UDPglucuronosyltrans–ferase activity was also enhanced by both inducers. After trypsin digestion of microsomes UDPglucuronosyltransferase activity was significantly higher in rats on a high cholesterol diet than in those on standard diet. After treating the microsomes in vitro by various membrane perturbants it was found that 3–methylcholanthrene made the enzyme proteins less soluble than phenobarbitone. The results support the idea that cholesterol affects the activities of drug metabolizing enzymes, due to changes in the structure of microsomal membranes