Effect of arsenic on the metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice analyzed by LC-MS/MS

摘要

Epidemiological data have shown an increased risk of lung cancer in nonsmokers exposed to environmental tobacco smoke (ETS). Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is believed to play a significant role in lung cancer in smokers. NNK is a potent carcinogen in rodents, inducing primarily adenocarinoma of the lung, the most common type of lung cancer observed in nonsmokers. In addition, synergism between cigarette smoking and exposure to arsenic on lung carcinogenesis has been reported by several epidemiological studies. The carcinogenic potential of cigarette component NNK is closely related to the NNK metabolism and the DNA adducts formed by NNK metabolites. We have developed a rapid LC-ESI-MS/MS method for the analysis of NNK metabolites in mice urine. This method is capable of determining NNK and its five metabolites (NNK, NNAL, PBD, HPB, hydroxy acid, and keto acid) simultaneously and quantitatively. In a feeding experiment, male ICR mice were gavaged daily with NNK (0.5 mg/mouse) and 0, 10, or 20 mg/kg sodium arsenite for 9 days. Urine samples were collected for NNK metabolite analysis. Our results revealed that As co-treatment increased the levels of urinary products of NNK metabolic activation pathway (alpha-hydroxylation), but not those of detoxification pathway (glucuronidation), suggesting that exposure to As would increase the metabolic activation of NNK and hence its carcinogenicity in mice.