CIPROFIBRATE, A CARCINOGENIC PEROXISOME PROLIFERATOR, INCREASES THE PHOSPHORYLATION OF EPIDERMAL-GROWTH-FACTOR RECEPTOR IN ISOLATED RAT HEPATOCYTES

Ciprofibrate, a hypolipidaemic drug with carcinogenic and peroxisome-p roliferation effects in rat liver, was found to increase the phosphory lation of epidermal-growth-factor receptor in P-32-labeled isolated ra t hepatocytes. This effect was suppressed by protein-kinase-C inhibito rs, and was accompanied by an almost complete inhibition of the recept or autophosphorylation normally induced by its ligand. However, in vit ro experiments showed that protein-kinase-C phosphorylation of purifie d epidermal-growth-factor receptor was activated by ciprofibroyl-CoA, the acyl-CoA derivative of the drug, but not by the unmodified drug. N either compound affected the ligand induction of epidermal-growth-fact or-receptor autophosphorylation in isolated liver membranes. These res ults suggest that metabolically produced ciprofibroyl-CoA in liver cel ls would activate protein-kinase-C and produce changes in epidermal-gr owth-factor-receptor function.