Role of oxidative DNA damage caused by carbon tetrachloride-induced liver injury – enhancement of MeIQ-induced glutathione S-transferase placental form-positive foci in rats

The strong association between chronic inflammation and development of cancer is well-established in chronic inflammatory states. Nitric oxide (NO) is generated by inflammatory cytokines due to the action of inducible nitric oxide (iNOS), oxidizing DNA to form 8-hydroxy-2′-deoxyguanosine (8-OHdG) adducts, a major species of oxidative DNA damage. In the present study, we investigated the enhancing effect of carbon tetrachloride, a typical hepatotoxic chemical, on rat 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) hepato-carcinogenesis. A total of 420, 21-day-old, male Fisher 344 rats were given MeIQx at a concentration of 0, 0.001 ppm (human exposure level), 0.01, 0.1, 1, 10 and 100 ppm in the diet, and each group was separated into carbon tetrachloride-treated and vehicle-treated subgroups. Carbon tetrachloride was given by subcutaneous (s.c.) injection twice a week at a dose of 0.125 ml/kg body weight (b.w.) for the first 10 weeks and then at 0.25 ml/kg b.w. during the next 10 weeks. All rats were sacrificed at the end of week 22. In the vehicle-treated animals, only 100 ppm MeIQx significantly increased the number of glutathione S-transferase placental form (GST-P)-positive foci in the liver compared with 0 ppm MeIQx. Co-administration of carbon tetrachloride enhanced the induction of GST-P-positive foci by MeIQx in each group and the curve was almost the same pattern as that of vehicle-treated group but their numbers were significantly enhanced with 10 ppm and above compared with 0 ppm MeIQx. Persistent liver injury and liver cell proliferation were histopathologically observed in carbon tetrachloride-treated groups. Increase of 8-hydroxydeoxyguanosine (8-OHdG) formation and iNOS overexpression were observed by co-administration of carbon tetrachloride in MeIQx-treated rat liver. Our results indicate that carbon tetrachloride enhances MeIQx hepato-carcinogenicity through increase in oxidative DNA damage but non-effect levels of MeIQx carcinogenic activity still exist.