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Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.

ABSTRACT: A locus at 15q24/15q25.1, which includes the nicotinic acetylcholine receptor A subunits 3 and 5 (CHRNA3 and CHRNA5) genes, has recently been associated with lung cancer risk, self-reported number of cigarettes smoked per day, and a nicotine dependence scale. It is not clear whether the association with lung cancer is direct or mediated through differences in smoking behavior. We used urinary biomarkers to test whether two linked lung cancer risk variants in CHRNA3 (rs1051730) and CHRNA5 (rs16969968) are associated with intensity of smoking and exposure to a tobacco-specific carcinogenic nitrosamine per cigarette dose. We studied 819 smokers and found that carriers of these variants extract a greater amount of nicotine (P = 0.003) and are exposed to a higher internal dose of 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (P = 0.03) per cigarette than noncarriers. Thus, smokers who carry the CHRNA3 and CHRNA5 variants are expected to be at increased risk for lung cancer compared with smokers who do not carry these alleles even if they smoked the same number of cigarettes. Number of cigarettes per day, even if it could be accurately assessed, is not an adequate measure of smoking dose.

SUBMITTER: Le Marchand L

PROVIDER: S-EPMC2587068 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.

Le Marchand Loïc L Derby Kiersten S KS Murphy Sharon E SE Hecht Stephen S SS Hatsukami Dorothy D Carmella Steven G SG Tiirikainen Maarit M Wang Hansong H

Cancer research 20081101 22

A locus at 15q24/15q25.1, which includes the nicotinic acetylcholine receptor A subunits 3 and 5 (CHRNA3 and CHRNA5) genes, has recently been associated with lung cancer risk, self-reported number of cigarettes smoked per day, and a nicotine dependence scale. It is not clear whether the association with lung cancer is direct or mediated through differences in smoking behavior. We used urinary biomarkers to test whether two linked lung cancer risk variants in CHRNA3 (rs1051730) and CHRNA5 (rs1696 ...[more]

PMID: 19010884

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Project description:BackgroundIdentifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo.MethodsWithin UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles.ResultsCorrecting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008-0.04) and cotinine (P = <0.001-0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02-0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007-0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02-0.03) variants in African Americans were nominally associated with NNAL glucuronidation.ConclusionsFindings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation.ImpactFindings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94-104. ©2014 AACR.

Project description:IntroductionAcrolein is a highly ciliatoxic agent, a toxic respiratory irritant, a cardiotoxicant, and a possible carcinogen present in tobacco smoke including hookah tobacco.Methods105 hookah smokers and 103 non-smokers attended exclusively hookah smoking social events at either a hookah lounge or private home, and provided urine samples the morning of and the morning after the event. Samples were analyzed for 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein.ResultsGeometric mean (GM) urinary 3-HPMA levels in hookah smokers and non-smokers exposed to secondhand smoke (SHS) increased significantly, 1.41 times, 95% CI = 1.15 to 1.74 and 1.39 times, 95% CI = 1.16 to 1.67, respectively, following a hookah social event. The highest increase (1.68 times, 95% CI = 1.15 to 2.45; p = 0.007) in 3-HPMA post a hookah social event was among daily hookah smokers (GM, from 1991 pmol/mg to 3348 pmol/mg). Pre-to-post event change in urinary 3-HPMA was significantly positively correlated with pre-to-post event change in urinary cotinine among hookah smokers at either location of hookah event, (ρ = 0.359, p = 0.001), and among non-smokers in hookah lounges (ρ = 0.369, p = 0.012).ConclusionsHookah tobacco smoke is a source of acrolein exposure. Findings support regulating hookah tobacco products including reducing humectants and sugar additives, which are precursors of acrolein under certain pyrolysis conditions. We suggest posting health warning signs for indoor smoking in hookah lounges, and encouraging voluntary bans of smoking hookah tobacco in private homes.ImplicationsOur study is the first to quantify the increase in acrolein exposure in hookah smokers and non-smokers exposed to exclusively hookah tobacco SHS at hookah social events in homes or hookah lounges. Our findings provide additional support for regulating hookah tobacco product content, protecting non-smokers' health by posting health warning signs for indoor smoking in hookah lounges, and encouraging home bans on hookah tobacco smoking to safeguard vulnerable residents.

Dataset Information

Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.

Publications

Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.

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