Induction of hamster hepatic peroxisomal beta-oxidation and peroxisome proliferation-associated 80000 mol. wt. polypeptide by hypolipidemic drugs

Abstract

1 The effects of hypolipidemic drugs fenofibrate (isopropyl[4-(p-chlorobenzoyl)-2-phenoxy-2-methyl]propionate), pyrinixil (BR-931; [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide]), methyl clofenapate (2-methyl-2[4-(p-chlorophenyl)phenoxy] 2-methyl-propionate), and clofibrate (ethyl alpha-p-chloro-phenoxyisobutyrate) on plasma triglyceride levels, hepatic peroxisome proliferation and peroxisome-associated enzymes in hamsters were investigated. 2 Fenofibrate, pyrinixil and methyl clofenapate were administered in the diet at 0.2% level (w/w) for 6 weeks. Clofibrate was fed at 0.5% level. 3 Fenofibrate, pyrinixil and methyl clofenapate induced a marked proliferation of peroxisomes in hamster liver cells which was comparable to that observed in the rat and mouse liver, whereas the peroxisome proliferative effect of clofibrate was less pronounced. Peroxisomal fatty acid beta-oxidation system was found in the hamster liver and its activity was enhanced significantly by hypolipidemic drugs. The magnitude of induction of [1(-14)C]palmitoyl CoA oxidation, heat-labile enoyl-CoA hydratase and peroxisome proliferation-associated 80000 mol. wt. polypeptide in the hamster appeared to parallel the extent of peroxisome proliferation. 4 All four hypolipidemic compounds increased hepatic catalase and carnitine acetyltransferase activities and decreased plasma triglyceride levels in the hamster. The observed hepatic effects of hypolipidemic drugs in hamster are identical to those induced by peroxisome proliferators in the rat and mouse. 5 These observations suggest that hypolipidemic agents identified as peroxisome proliferators in rats, mice and now hamsters would very likely enhance the peroxisomal enzyme system in other species. Additional information on the interspecies responses to peroxisome proliferators, however, is necessary to assess the role of peroxisome proliferation in carcinogenesis.