Low ratio of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol-glucuronides (NNAL-Gluc)/free NNAL increases urothelial carcinoma risk

Cigarette smoking is the most important risk factor for bladder cancer. The compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are viewed as biomarkers for cigarette smoking exposure. Therefore, we wanted to explore the effects of these urinary metabolites on urothelial carcinoma (UC) risk. We recruited 127 pairs of UC cases and matched healthy participants for a hospital-based case-control study. Participants completed questionnaires of medical and social information, including smoking history, and provided 50 mL urine samples. Urine samples were analyzed for free NNAL and NNAL-Gluc using the liquid chromatography-tandem mass spectrometry method. Nonparametric analysis and multivariate logistic regression were applied to compare the differences in NNK-related metabolites between UC cases and controls, and to estimate the UC risk associated with certain risk factors. Overall, controls with higher cumulative cigarette smoking exposure had higher total NNAL, free NNAL and NNAL-Gluc. In addition, a decreased NNAL-Gluc/free NNAL ratio corresponded to a significantly increased UC risk. The association between the NNAL-Gluc/free NNAL ratio and UC risk was significant in a dose-response manner. Furthermore, cumulative cigarette smoking exposure was found to interact significantly with low NNAL-Gluc/free NNAL ratio to affect UC risk in this study. This is the first study to conclude that the metabolic products of total NNAL, free NNAL and NNAL-Gluc might be measured as biomarkers of cigarette smoking exposure. Furthermore, the NNAL-Gluc/free NNAL ratio was a better biomarker to evaluate UC risk than total NNAL.