title: Combined ascorbic acid and sodium nitrite treatment induces oxidative DNA damage-associated mutagenicity in vitro, but lacks initiation activity in rat forestomach epithelium.
abstract: Combination treatment with sodium nitrite (NaNO(2)) and ascorbic acid (AsA) is well known to promote forestomach carcinogenesis in rats and weakly enhance esophageal carcinogenesis under acid reflux conditions. Nitric oxide generation and oxidative DNA damage are considered to be related to the enhancement of carcinogenesis. The purpose of the present study was to investigate whether oxidative DNA damage-associated genotoxicity and tumor initiating potential are involved in the carcinogenesis. In the bacterial reverse mutation assay using Escherichia coli deficient in the mutM gene encoding 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase, the combination with NaNO(2) and AsA increased the mutation frequency dramatically, slight increase being evident in the parental strain. In vivo, a significant increase in 8-OHdG levels in the rat forestomach epithelium occurred at 24 h after combined treatment. Six-week-old F344 male rats were given drinking water containing 0.2% NaNO(2) and a diet supplemented with 1% AsA in combination, or the chemicals individually or basal diet alone for 12 weeks. After an interval of 2 weeks, they received 1% butylated hydroxyanisole in the diet for promotion until the end of weeks 52 and 78. Although one squamous cell carcinoma was observed in the combined group, there was no significant variation in tumor development among the groups. The study indicated that the combination of NaNO(2) with AsA induces genotoxicity due to oxidative DNA damage in vitro, and elevates 8-OHdG levels in the forestomach epithelium, but lacks initiating activity in the rat two-stage carcinogenesis model.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Setagaya-Ku, Tokyo 158-8501, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kuroiwa
authors.forename: Masami
authors.initials: M
authors.lastname: Yamada
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsui
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Masumura
authors.forename: Masako
authors.initials: M
authors.lastname: Tasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Masao
authors.initials: M
authors.lastname: Hirose
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D001205:Ascorbic Acid / Q000633:toxicity*; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D004249:DNA Damage; D004269:DNA, Bacterial / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D009153:Mutagens / Q000633:toxicity*; D030781:Organisms, Genetically Modified; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012977:Sodium Nitrite / Q000633:toxicity*; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D002273:Carcinogens; D004269:DNA, Bacterial; D009153:Mutagens; D008769:Methylnitronitrosoguanidine; D002083:Butylated Hydroxyanisole; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D012977:Sodium Nitrite; D001205:Ascorbic Acid