The effect of hypolipidaemic agents on peroxisomal beta-oxidation and mixed-function oxidase activities in primary cultures of rat hepatocytes. Relationship between induction of palmitoyl-CoA oxidation and lauric acid hydroxylation.

A study was conducted of the effects of 10 hypolipidaemic agents on peroxisomal and microsomal enzyme activities in primary cultures of rat hepatocytes. Treatment with compounds such as Wy-14,643, tiadenol, nafenopin, BR-931, clofibrate and mono-(2-ethylhexyl)phthalate induced cyanide-insensitive palmitoyl-CoA oxidation (a specific peroxisomal marker enzyme), a polypeptide with a molecular weight of 80,000 associated with peroxisome proliferation, and carnitine acetyltransferase activity, after 70 h of culture. These compounds also maintained hepatocyte cytochrome P-450 levels and markedly induced lauric acid hydroxylation, whereas little effect was observed on 7-ethoxycoumarin O-deethylase. Studies with metyrapone, which also maintains cytochrome P-450, suggested that treatment with the hypolipidaemic agents resulted in the formation of different form(s) of cytochrome P-450 to those present in control cultures. Regression analysis demonstrated a high correlation between the induction of the peroxisomal parameters and lauric acid hydroxylation. The results indicate that hypolipidaemic agents which stimulate hepatic peroxisomal enzyme activities also induce novel form(s) of cytochrome P-450 with high specificity towards lauric acid hydroxylation. Both these processes may depend therefore on common receptor(s) which are retained in primary cultures of rat hepatocytes.