title: 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.
abstract: 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.
authors.affiliation: Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Iwai
authors.forename: Rezaul
authors.initials: R
authors.lastname: Karim
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Kitano
authors.forename: Toshio
authors.initials: T
authors.lastname: Sukata
authors.forename: Wei
authors.initials: W
authors.lastname: Min
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Seki
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D017931:DNA Primers / Q000737:chemistry; D043382:DNA-Formamidopyrimidine Glycosylase; D005982:Glutathione Transferase / Q000378:metabolism*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010920:Placenta / Q000201:enzymology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000637:Transaminases / Q000097:blood
chemical_list: D002273:Carcinogens; D017931:DNA Primers; D011810:Quinoxalines; D006151:Guanosine; C046215:8-hydroxyguanosine; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D004247:DNA; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005982:Glutathione Transferase; D000637:Transaminases; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D001973:Bromodeoxyuridine