Alaska Native smokers and smokeless tobacco users with slower CYP2A6 activity have lower tobacco consumption, lower tobacco-specific nitrosamine exposure and lower tobacco-specific nitrosamine bioactivation

University of Toronto, Departments of Psychiatry, Pharmacology and Toxicology, Centre for Addiction & Mental Health, Toronto, Ontario, Canada.
Carcinogenesis (Impact Factor: 5.33). 10/2012; 34(1). DOI: 10.1093/carcin/bgs306
Source: PubMed


Nicotine, the psychoactive ingredient in tobacco, is metabolically inactivated by CYP2A6 to cotinine. CYP2A6 also activates procarcinogenic tobacco-specific nitrosamines (TSNA). Genetic variation in CYP2A6 is known to alter smoking quantity and lung cancer risk in heavy smokers. Our objective was to investigate how CYP2A6 activity influences tobacco consumption and procarcinogen levels in light smokers and smokeless tobacco users. Cigarette smokers (n=141), commercial smokeless tobacco users (n=73), and iqmik users (n=20) were recruited in a cross-sectional study of Alaska Native people. The participant' CYP2A6 activity was measured by both endophenotype and genotype, and their tobacco and procarcinogen exposure biomarker levels were also measured. Smokers, smokeless tobacco users and iqmik users with lower CYP2A6 activity had lower urinary total nicotine equivalents (TNE) and NNAL levels (a biomarker of TSNA exposure). Levels of NNN, a TSNA metabolically bioactivated by CYP2A6, were higher in smokers with lower CYP2A6 activities. Light smokers and smokeless tobacco users with lower CYP2A6 activity reduce their tobacco consumption in ways (e.g. inhaling less deeply) that are not reflected by self-report indicators. Tobacco users with lower CYP2A6 activity are exposed to lower procarcinogen levels (lower NNAL levels) and have lower procarcinogen bioactivation (as indicated by the higher urinary NNN levels suggesting reduced clearance), which is consistent with a lower risk of developing smoking related cancers. This study demonstrates the importance of CYP2A6 in the regulation of tobacco consumption behaviors, procarcinogen exposure and metabolism in both light smokers and smokeless tobacco users.

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Available from: Matthew John Binnington, Jul 06, 2015
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    • "C ytochrome P450 2A6 (CYP2A6) is a phase I drug metabolizing enzyme, expressed almost only in the liver . It is involved in the metabolism of steroids and fatty acids as well as activation of procarcinogenes (Tomaszewski et al., 2008; Zhu et al., 2013). CYP2A6 contributes to disposition of nicotine, cotinine, coumarin, and some clinically important drugs including antiretrovirals and antimalarial drugs (Newton et al., 2000; Ogburn et al., 2010; Pelkonen et al., 2000). "
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    ABSTRACT: BACKGROUND: Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine and carcinogen exposure. However a given cotinine level may not represent the same tobacco exposure; for example, African Americans have higher cotinine levels than Caucasians after controlling for exposure. METHODS: Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal were measured in non-smoking Caucasians (Study 1, n=181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n=163). RESULTS: Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P=0.01), or 1.39 and 1.12 in males and females (P=0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by ≥25% in CYP2A6 reduced metabolizers (≈2 fold between some genotypes) and in males. CONCLUSIONS: In people with slower, relative to faster, CYP2A6 activity cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure. Impact: Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e. African Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels) or between the sexes.
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    ABSTRACT: BACKGROUND AND AIMS: Gene variants in CHRNA5-A3-B4, which encode for the α5, α3 and β4 nicotinic receptor subunits, are associated with altered smoking behaviors in European-Americans. Little is known about CHRNA5-A3-B4 and its association with smoking behaviors and weight in Alaska-Native people, which is a population with high prevalence but low levels of tobacco consumption, extensive smokeless tobacco use, and high rates of obesity. We investigated CHRNA5-A3-B4 haplotype structure and its association with nicotine intake and obesity in Alaska-Native people. DESIGN, SETTING, PARTICIPANTS: A cross sectional study of 400 Alaska-Native individuals including 290 tobacco users. MEASUREMENTS: CHRNA5-A3-B4 genotype, body weight, and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE). FINDINGS: Alaska-Native people have a distinct CHRNA5-A3-B4 haplotype structure compared with European/African-Americans. In 290 Alaska-Native tobacco users, the 'G' allele of rs578776, which tagged a 30kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and significantly associated with nicotine intake (20% higher plasma cotinine, P<0.001, 16% higher TNE, P=0.076), while rs16969968 was not associated with nicotine intake. Rs578776 acted in combination with CYP2A6, the main nicotine-metabolizing enzyme, to increase nicotine intake by 1.8 fold compared with the low risk group (P<0.001). Furthermore rs2869950, a single nucleotide polymorphism 5' to CHRNB4, was significantly associated with increased body mass index (P<0.01) in the tobacco users even after controlling for differences in nicotine intake (P<0.01). CONCLUSIONS: Genetic variants in CHRNA5-A3-B4 alter nicotine intake and body mass index in a population of Alaska-Native people, who have a distinct haplotype structure, smoking behaviors and prevalence of obesity.
    No preview · Article · May 2013 · Addiction
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