title: Enhancements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism and carcinogenic risk via NNK/arsenic interaction.
abstract: Epidemiological studies indicated an enhancement of cigarette smoke-induced carcinogenicity, including hepatocellular carcinoma, by arsenic. We believe that arsenic will enhance the expression of hepatic CYP2A enzyme and NNK metabolism (a cigarette smoke component), thus its metabolites, and carcinogenic DNA adducts. Male ICR mice were exposed to NNK (0.5 mg/mouse) and sodium arsenite (0, 10, or 20 mg/kg) daily via gavaging for 10 days and their urine was collected at day 10 for NNK metabolite analysis. Liver samples were also obtained for CYP2A enzyme and DNA adducts evaluations. Both the cyp2a4/5 mRNA levels and the CYP2A enzyme activity were significantly elevated in arsenic-treated mice liver. Furthermore, urinary NNK metabolites in NNK/arsenic co-treated mice also increased compared to those treated with NNK alone. Concomitantly, DNA adducts (N(7)-methylguanine and O(6)-methylguanine) were significantly elevated in the livers of mice co-treated with NNK and arsenic. Our findings provide clear evidence that arsenic increased NNK metabolism by up-regulation of CYP2A expression and activity leading to an increased NNK metabolism and DNA adducts (N(7)-methylguanine and O(6)-methylguanine). These findings suggest that in the presence of arsenic, NNK could induce greater DNA adducts formation in hepatic tissues resulting in higher carcinogenic potential.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan, ROC.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Lee
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
authors.forename: Jui-Pin
authors.initials: JP
authors.lastname: Wu
authors.forename: Yune-Fang
authors.initials: YF
authors.lastname: Ueng
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.forename: Dennis Paul Hsientang
authors.initials: DP
authors.lastname: Hsieh
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
mesh_terms: D000818:Animals; D001151:Arsenic / Q000378:metabolism*; D001835:Body Weight; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts; D006128:Growth; D006900:Hydroxylation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009602:Nitrosamines / Q000378:metabolism* / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D009602:Nitrosamines; D012333:RNA, Messenger; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System; D001151:Arsenic