CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolism of nicotine and the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 197 lung cancer cases and 197 matched controls was conducted within a prospective cohort of 63 257 Chinese men and women in Singapore. Quantified were five genetic variants of <span style="font-style:italic;">CYP2A6</span> (<span style="font-style:italic;">*1A</span>, <span style="font-style:italic;">*4, *7, *9</span> and <span style="font-style:italic;">*12</span>) and urinary metabolites of nicotine [total nicotine, total cotinine, total <span style="font-style:italic;">trans-3′</span>-hydroxycotinine (3HC)] and NNK (total NNAL, free NNAL, NNAL-glucuronide, NNAL-<span style="font-style:italic;">N</span>-glucuronide, and NNAL-<span style="font-style:italic;">O</span>-glucuronide). Higher urinary metabolites of nicotine and NNK were significantly associated with a 2- to 3-fold increased risk of lung cancer after adjustment for smoking intensity and duration. Lower <span style="font-style:italic;">CYP2A6</span>-determined nicotine metabolizer status was significantly associated with a lower ratio of total 3HC over total cotinine, lower total nicotine equivalent and reduced risk of developing lung cancer (all <span style="font-style:italic;">P</span>_trend < 0.001). Compared with normal metabolizers, odds ratios (95% confidence intervals) of developing lung cancer for intermediate, slow and poor metabolizers determined by <span style="font-style:italic;">CYP2A6</span> genotypes were 0.85 (0.41–1.77), 0.55 (0.28–1.08) and 0.32 (0.15–0.70), respectively, after adjustment for smoking intensity and duration and urinary total nicotine equivalents. Thus the reduced risk of lung cancer in smokers with lower CYP2A6 activity may be explained by lower consumption of cigarettes, less intense smoking and reduced CYP2A6-catalyzed activation of the tobacco-specific lung carcinogen NNK.</span>

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