Joint effect of arsenic methylation profile and NNK metabolites on urothelial carcinoma

Purpose: Cigarette smoking interacts with the urinary arsenic profile to modify the risk of urothelial carcinoma. NNK (4-[methylnitrosamino]-1-[3- pyridyl]-1-butanone) and its metabolite NNAL (4-[methylnitrosamino]-1-[3- pyridyl]-1-butanol) are biomarkers for cigarette smoking exposure. We explored the joint effects of urinary NNK metabolites and arsenic species on urothelial carcinoma risk. Materials and Methods: We recruited 137 pairs of urothelial carcinoma cases and matched healthy participants for a hospital based case-control study. Participants completed questionnaires and provided 50 ml urine samples. Urine samples were analyzed for free NNAL and NNAL-glucuronides using liquid chromatography-tandem mass spectrometry. Samples were analyzed for arsenic species using high performance liquid chromatography hydride generator atomic absorption spectrometry. Results: Overall, subjects with high urinary total NNAL and high total arsenic had a greater urothelial carcinoma risk than those with a low total NNAL and low total arsenic. Subjects with a lower ratio of NNAL-glucuronides-to-free NNAL and higher total arsenic had a greater urothelial carcinoma risk than those with a higher NNAL-glucuronides-to-free NNAL ratio and lower total arsenic. Conclusions: This is the first study to our knowledge to demonstrate a significant trend of progressively increased risk of urothelial carcinoma in subjects who had none, one or both of the factors of urinary total arsenic and total NNAL or urinary total arsenic and the ratio of NNAL-glucuronides-to-free NNAL.