Evidence for an intensity-dependent interaction of NAT2 acetylation genotype and cigarette smoking in the Spanish Bladder Cancer Study

Abstract

Background: The N-acetyltransferase 2 (NAT2) enzyme detoxifies aromatic amines, an important class of carcinogens in tobacco smoke. Slow acetylation phenotype individuals have reduced detoxification capacity compared with those with a rapid/intermediate phenotype. Analysis of the Spanish Bladder Cancer Study found an odds ratio (OR) for slow acetylators relative to rapid/intermediate acetylators of 0.9 in never-smokers and 1.6 in ever-smokers, a 1.8-fold enhancement in smokers. Evidence indicates that acetylation is an exposure-dependent process, and thus the magnitude of the interaction may also depend on exposure level.

Methods: We extend a comprehensive three-parameter linear-exponential model for the excess odds ratio (EOR) for smoking to include effects of NAT2 status, and reanalyse smoking and NAT2 status for the bladder cancer data.

Results: We show that variations in smoking risk with NAT2 status result from interactions with smoking intensity (cigarettes per day) and not total pack-years of exposure. In addition, the relative increase in smoking risk in NAT2 slo acetylators increases with smoking intensity.

Conclusions: Analyses reveal an enhanced effect for smoking intensity and bladder cancer in NAT2 slow acetylators which increases with intensity.