Lack of induction of hepatic DNA damage on long-term administration of peroxisome proliferators in male F-344 rats

Abstract

In order to evaluate the relationship between hydrogen peroxide (H 2O 2) generation and subsequent DNA damage caused by peroxisome proliferaton, we examined DNA damage and changes in peroxisomal isomal β-oxidation activty in rat liver. Male F-344 rats were given orally clofibrate, bezafibrate or di(2-ethylhexyl)phthalate (DEHP) for up to 78 weeks. In rats fed DEHP for 52 or 78 weeks hepatocarcinomas or neoplastic nodules were found. In rats treated for 2 weeks with peroxisome proliferations, peroxisomal β-oxidation activity was increased 10–17 times over control levels. After long-term treatment (20–78 weeks), the level of peroxisomal β-oxidation activity remained 3–13-times higher in each group. When single strand DNA breaks were measured by a DNA-alkaline elution technique, no increase in DNA damage was observed in livers from rats fed peroxisome proliferators for 2, 40 or 78 weeks. In rats bearing hepatocarcinomas induced by DEHP, the hepatic DNA showed significant breaks; the rate of DNA-alkaline elution was found to increase approximately 5-fold. No significant increase in hepatic liquid peroxide level was observed in each group. These results show that although prolonged treatment with peroxisome proliferators induces markedly peroxisomal β-oxidation activity, the active oxygen species from peroxisomal β-oxidation are not enough to give rise to significant DNA damage. Moreover, the change in the activity of peroxisomal β-oxidation may not relate to hepatocarcinogenesis induced by peroxisome proliferators.