Enhancements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism and carcinogenic risk via NNK/arsenic interaction.
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.
Lee
Hui-Ling
HL
Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan, ROC.
Chang
Louis W
LW
Wu
Jui-Pin
JP
Ueng
Yune-Fang
YF
Tsai
Ming-Hsien
MH
Hsieh
Dennis Paul Hsientang
DP
Lin
Pinpin
P
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
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