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‐proliferation effects in rat liver, was found to increase the phosphorylation of epidermal‐growth‐factor receptor in ³²P‐labeled isolated rat hepatocytes. This effect was suppressed by protein‐kinase‐C inhibitors, and was accompanied by an almost complete inhibition of the receptor autophosphorylation normally induced by its ligand. However, in vitro experiments showed that protein‐kinase‐C phosphorylation of purified epidermal‐growth‐factor receptor was activated by ciprofibroyl‐CoA, the acyl‐CoA derivative of the drug, but not by the unmodified drug. Neither compound affected the ligand induction of epidermal‐growth‐factor‐receptor autophosphorylation in isolated liver membranes. These results suggest that metabolically produced ciprofibroyl‐CoA in liver cells would activate protein‐kinase‐C and produce changes in epidermal‐growth‐factor‐receptor function.