DELAYED-EFFECTS OF CIPROFIBRATE ON RAT-LIVER PEROXISOMAL PROPERTIES AND PROTOONCOGENE EXPRESSION

Peroxisome proliferators (PPs) are non-genotoxic carcinogens in rodent s. Their reversible effects on rat liver have been studied with ciprof ibrate and fenofibrate. We found that with the hypolipemic drug fenofi brate a pause of 28 days is sufficient for a return to normal status, whereas with the highly potent PP ciprofibrate the stimulation of ACO mRNA levels remains after its withdrawal. We investigated the effects of the renewal of the treatment with PPs on other peroxisomal paramete rs and proto-oncogene expression using Wistar rats. interestingly, c-m yc expression was enhanced even upon drug withdrawal, and was more sti mulated by the second exposure to ciprofibrate, while c-fos expression was unaltered. However, only slight differences in c-Ha-ras expressio n were observed. Therefore, the effects of PPs in the Wistar rats are not totally reversible within 28 days following withdrawal, depending on the drug used. These delayed effects of ciprofibrate could be a key to our understanding the hepatocarcinogenic effect of PPs in rodents.