4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is correlated with 8-hydroxy-2'-deoxyguanosine in humans after exposure to environmental tobacco smoke

Cigarette smoking and exposure to environmental tobacco smoke (ETS) are important risk factors for many cancers. However, exposure doses have usually not been quantitatively assessed in human studies. In humans 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronate conjugate (defined as total NNAL) are the major metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a cigarette-specific carcinogen. Although animal studies have shown that exposure to cigarette smoke increases tissue oxidative DNA damage, the relationship between cigarette smoke and 8-hydroxydeoxyguanosine (8-OHdG) is not consistent in human studies. In the present study, we have developed a simple, sensitive, and robust LC-MS/MS method for quantifying total NNAL and 8-OHdG concentrations in human plasma. We quantified total NNAL and 8-OHdG in plasma as well as 8-OHdG in urine of 121 healthy male subjects. Total NNAL levels were significantly higher in ever-smokers than in never-smokers. Furthermore, total NNAL levels in plasma were increased with numbers of cigarettes smoked per day in ever-smokers. It suggests that total NNAL in plasma is a good biomarker for cigarette smoke exposure. After stratifying by smoking status and adjusting for age, ETS exposure and occupation category, total NNAL was associated with plasma and urinary 8-OHdG in never-smokers, but not in ever-smokers. Since total NNAL levels in nonsmokers represented the ETS exposure, it appears that 8-OHdG levels are dose-dependently correlated with their ETS exposure dose. Furthermore, this correlation supports the hypothesis that oxidative DNA damage is one of major adverse effects induced by ETS exposure in humans.