title: Oxidative DNA damage and in vivo mutagenicity caused by reactive oxygen species generated in the livers of p53-proficient or -deficient gpt delta mice treated with non-genotoxic hepatocarcinogens.
abstract: Oxidative stress is thought to participate in chemical carcinogenesis and may trigger gene mutations. To accurately assess the carcinogenesis risk posed to humans by chemical exposure, it is important to understand the pathways by which reactive oxygen species (ROS) are generated and the effects of the resulting oxidative stress. In the present study, p53-proficient and -deficient gpt delta mice were given pentachlorophenol (PCP), phenobarbital (PhB) or piperonyl butoxide (PBO), which are classified as non-genotoxic hepatocarcinogens in rodents, at the respective carcinogenic doses for 13 weeks. Exposure to PCP or PBO, but not PhB, invoked significant increases in liver DNA 8-hydroxydeoxyguanosine (8-OHdG) levels. Treatment with PCP significantly increased mRNA levels of the gene encoding NAD(P):quinone oxidoreductase 1 (NQO1) in the liver, suggesting that redox cycling of the PCP metabolite tetrachlorohydroquinone gave rise to ROS. Exposure to PhB or PBO significantly elevated CYP 2B10 mRNA levels while NQO1 levels were also significantly increased in PBO-treated mice. Therefore, in addition to involvement of the CYP catalytic pathway in the ROS-generated system of PBO, catechol derivatives produced from the opening of the PBO functional group methylenedioxy ring probably resulted in ROS generation. However, PCP, PBO and PhB failed to increase gpt and red/gam gene mutations in the liver independently of p53. Overall, the action of oxidative stress by ROS derived from the metabolism of these carcinogens might be limited to cancer-promoting activity, which supports the previous classification of these carcinogens as non-genotoxic.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Tasaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kuroiwa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Inoue
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hibi
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsushita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Soichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010430:Pentosyltransferases / Q000235:genetics*; D000091402:Prohibitins; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002273:Carcinogens; D029968:Escherichia coli Proteins; C000717328:PHB protein, human; D000091402:Prohibitins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D010430:Pentosyltransferases; C071962:Gpt protein, E coli