Excessive Accumulation of Autofluorescent Lipofuscin in the Liver during Hepatocarcinogenesis by Methyl Clofenapate and Other Hypolipidemic Peroxisome Proliferators1

Several hypolipidemic drugs and certain industrial plasticizers induce proliferation of peroxisomes and enhance the activ ities of peroxisome-associated enzymes in the livers of rodents. Evidence now suggests that potent hepatic peroxisome proliferators as a class are carcinogenic, although they do not appear to be mutagenic in the Sa/mor>e//a-microsome assay system. We now report that long-term administration of methyl2-{4-(p-chlorophenyl)phenoxy]-2-methylpropionate, a potent hepatic peroxisome proliferator, at a dietary concentration of 0.1% (w/w), induced hepatocellular carcinomas in 14 of 14 male F344 rats between 65 and 75 weeks. The tumor cells contained several peroxisomes. Consistent with this observa tion was the finding of increased levels of carnitine acetyltransferase, heat-labile peroxisomal enoyl coenzyme hydratase, and peroxisomal /8-oxidation system in the tumors. As expected, methyl clofenapate was not mutagenic in the Sa/mone//a-microsome assay using Salmonella typhimurium strains TA98 and TA100. Abundant accumulation of autofluorescent lipofuscin in the nontumorous portions of liver in rats bearing methyl-2-[4-( pchlorophenyl)phenoxy]-2-methylpropionate-induced hepato cellular carcinomas was observed. The examination in this study of livers of rats bearing hepatocellular carcinomas in duced previously by five other hypolipidemic peroxisome proliferators provided retrospective evidence for increased accu mulation of autofluorescent pigment in the liver cells. It is suggested that accumulation of lipofuscin in the livers of rats fed peroxisome proliferators serves as evidence for the in creased production of biologically damaging free radicals as a result of H2O2 generated by sustained proliferation of peroxi somes. The hypothesis that persistent proliferation of peroxi somes and increase in peroxisomal /J-oxidation system serves as endogenous initiator of the neoplastic transformation of liver cells by increasing the intracellular production of DMA-dam aging H2O2 and other reactive oxygen intermediates (OH-, O2T, 1O2)remains to be tested.