Inhibition of ciprofibrate-induced hepatocarcinogenesis in the rat by dimethylthiourea, a scavenger of hydroxyl radical

DNA damage caused by oxidative stress is considered to play an important ro le in peroxisome proliferator-induced hepatocarcinogenesis in rats and mice . In this study, we investigated the effect of dimethylthiourea (DMTU), a k nown hydroxyl radical scavenger, on ciprofibrate-induced hepatocarcinogenes is. Male F-344 rats were fed a diet containing 0.025% ciprofibrate and give n daily intraperitoneal injections of DMTU (5 days a week) at a dose of 50 or 250 mg/kg body weight for 60 weeks at which time the study was terminate d. Livers from all animals were analyzed grossly and microscopically for in cidence, number and type of tumors. All rats given ciprofibrate alone devel oped altered areas, neoplastic nodules (NN) and hepatocellular carcinomas ( HCC). Combined administration of ciprofibrate and DMTU resulted in inhibiti on of tumor development. In the group given higher doses of DMTU the incide nce of NN was 100% and HCC 0%. The number of tumors per liver also signific antly decreased (p<0.001). At lower dose levels DMTU caused significant red uction in the number of tumors per liver (p<0.05) and a slight reduction (2 9%) in the incidence of HCC. The inhibitory effect of DMTU on ciprofibrate- induced hepatocarcinogenesis could be explained by hydroxyl radical scaveng ing properties of DMTU, resulting in decreased free radical induced DNA dam age.