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Lack of DNA damage or lipid peroxidation measured in vivo in the rat liver following treatment with peroxisomal proliferators
Imperial Chemical Industries PLC, Central Toxicology Laboratory Alderley Park, Macclesfield, SK10 4TJ, UK
This study was undertaken to investigate the hypothesis linking peroxisome proliferation with the production of reactive oxygen species and subsequent DNA damage. Hepatic peroxisomal proliferation was induced in male Wistar-derived rats by the administration of clofibrate, methyl clofenapate, di(2-ethylhexyl)phthalate, or its metabolite mono (2-ethylhexyl)phthalate (MEHP) for periods of up to 28 days. Genotoxicity was monitored using an alkaline elution technique to assay for DNA strandbreaks and cytotoxicity was monitored by measuring lipid peroxidation. Both parameters might be expected to be elevated if peroxisome proliferation is accompanied by an elevated level of oxygen free radicals within the cell. Enzyme measurements made on the livers of the treated rats showed that peroxisomal palmitoyl CoA oxidase activity was markedly increased over control whereas peroxisomal catalase activity was not. In addition, both the cytosolic glutathione peroxidase and superoxide dismutase activities were found to be lowered in the treated animals by up to 50 and 20% respectively. Despite such changes in enzyme activity, no evidence for increases in DNA strandbreaks or lipid peroxidation was obtained with any of the chemicals at any of the time points examined. DNA strandbreaks were also assayed on hepatocytes treated in culture with MEHP (0.5 mM) for 3 days and then exposed to inhibitors of DNA repair for 2 h immediately before assay. Again, no significant increase over controls was observed. Our data suggest that any increase in radical production in the livers of rats exposed to peroxisome proliferators is not large enough to give rise to a biologically significant degree of DNA damage and that the mechanism whereby such chemicals produce liver tumours in certain rodent species may be one other than simply DNA damage due to increased production of radical species.
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