Comparative studies on di-(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation in the rat and hamster.
Young male Sprague-Dawley rats and Syrian hamsters were treated with 25-1000 mg/kg/day di-(2-ethylhexyl) phthalate (DEHP) orally for 14 days. Liver enlargement was observed in both species, the magnitude being greater in the rat than in the hamster. In the rat there was a marked dose-dependent induction of the peroxisomal marker cyanide-insensitive palmitoyl-CoA oxidation and also of carnitine acetyltransferase. Little effect was observed on the mitochondrial markers carnitine palmitoyltransferase and succinate dehydrogenase. Whereas in the rat, increased peroxisomal enzyme activities were observed after treatment with 100 and 250 mg/kg/day DEHP, much less effect was observed in the hamster even after 1000 mg/kg/day DEHP. Parallel morphological investigations demonstrated a greater increase in hepatic peroxisome numbers in the rat than in the hamster. 14C-labeled DEHP was found to be more rapidly hydrolyzed by rat than hamster hepatic and small intestinal mucosal cell preparations and differences were also observed in the absorption and excretion of oral doses of [14C]DEHP. Studies with mono-(2-ethylhexyl) phthalate (MEHP), a primary metabolite of DEHP, and a hypolipidemic drug clofibrate also resulted in a greater increase in hepatic peroxisomal enzymes in the rat compared to the hamster. The results demonstrate that while DEHP, MEHP, and clofibrate induced hepatic peroxisome proliferation in both species, there was a marked species difference in response. Comparative long-term studies in these species may thus help to clarify the role of peroxisome proliferation in the hepatocarcinogenicity of DEHP.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004051:Diethylhexyl Phthalate / Q000378:metabolism / Q000633:toxicity*; D004790:Enzyme Induction; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008647:Mesocricetus; D008830:Microbodies / Q000187:drug effects*; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D010795:Phthalic Acids; D004051:Diethylhexyl Phthalate