Article

The association of a tobacco-specific biomarker and cigarette consumption and its dependence on host characteristics

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Rockville, MD 20852, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 10/2007; 16(9):1852-7. DOI: 10.1158/1055-9965.EPI-07-0018
Source: PubMed

ABSTRACT The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen, which can be characterized by urinary concentrations of the metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL) and its glucuronide. Using baseline data in current smokers from four clinical trials, we examine the associations of urinary cotinine with CPD and of total NNAL with cotinine and the modification of these associations by several host factors. There was a linear relationship between ln(cotinine) and ln(CPD) within categories of the Fagerstrom Test of Nicotine Dependence and of age. The increasing trend was significantly smaller for subjects with high and very high nicotine addiction and for older subjects and larger in females than males. The regression of ln(total NNAL/cotinine) on ln(cotinine) declined linearly, suggesting reduced NNK uptake per unit cotinine with increasing cotinine. The decline in trend was greater in subjects with increased CPD, with greater nicotine addiction, and at older ages and was smaller in females, although gender differences were small. Variations in the ratio with host characteristics were generally similar to a recent epidemiologic analysis of effect modification of the association between lung cancer and cigarette smoking.

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    ABSTRACT: 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.
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