Delayed effects of ciprofibrate on rat liver peroxisomal properties and proto-oncogene expression

Peroxisome proliferators (PPs) are non-genotoxic carcinogens in rodents. Their reversible effects on rat liver have been studied with ciprofibrate and fenofibrate. We found that with the hypolipemic drug fenofibrate 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 parameters and proto-oncogene expression using Wistar rats. Interestingly, c-myc expression was enhanced even upon drug withdrawal, and was more stimulated by the second exposure to ciprofibrate, while c-fos expression was unaltered. However, only slight differences in c-Ha-ras expression 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.