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 role in peroxisome proliferator-induced hepatocarcinogenesis in rats and mice. In this study, we investigated the effect of dimethylthiourea (DMTU), a known hydroxyl radical scavenger, on ciprofibrate-induced hepatocarcinogenesis. Male F-344 rats were fed a diet containing 0.025% ciprofibrate and given 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 terminated. Livers from all animals were analyzed grossly and microscopically for incidence, number and type of tumors. All rats given ciprofibrate alone developed altered areas, neoplastic nodules (NN) and hepatocellular carcinomas (HCC). Combined administration of ciprofibrate and DMTU resulted in inhibition of tumor development. In the group given higher doses of DMTU the incidence of NN was 100% and HCC 0%. The number of tumors per liver also significantly decreased (p<0.001). At lower dose levels DMTU caused significant reduction in the number of tumors per liver (p<0. 05) and a slight reduction (29%) in the incidence of HCC. The inhibitory effect of DMTU on ciprofibrate-induced hepatocarcinogenesis could be explained by hydroxyl radical scavenging properties of DMTU, resulting in decreased free radical induced DNA damage.
Rao
M S
MS
Department of pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
Subbarao
V
V
D000818:Animals; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D004336:Drug Antagonism; D058607:Fibric Acids; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D020025:Peroxisome Proliferators / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D058607:Fibric Acids; D016166:Free Radical Scavengers; D020025:Peroxisome Proliferators; D002995:Clofibric Acid; C038983:1,3-dimethylthiourea; C019304:ciprofibrate; D013890:Thiourea