The Ability of Plasma Cotinine to Predict Nicotine and Carcinogen Exposure is Altered by Differences in CYP2A6: the Influence of Genetics, Race, and Sex
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/Aims: We examined in cigarette smokers whether cotinine was associated with depressive and/or anxiety disorders. Methods: Data were derived from 1,026 smoking adults with and without depressive and/or anxiety disorders participating in the Netherlands Study of Depression and Anxiety (NESDA). Depressive and anxiety disorders were ascertained with the DSM-IV Composite International Diagnostic Interview. Cigarette consumption was inquired about during an interview. Cotinine was assessed in plasma. Results: Currently depressed and/or anxious smokers (n = 692) reported smoking a higher number of cigarettes per day (CPD) than smokers with a remitted disorder (n = 190) and smokers with no lifetime disorder (n = 144). After controlling for CPD and other covariates, depressed and/or anxious smokers had lower cotinine levels compared to smokers with no lifetime disorder (B = -56.0, p = 0.001). In the full regression model, CPD was positively associated with cotinine levels, whereas current depression and/or anxiety and high body mass index were inversely associated with cotinine. Conclusion: After considering CPD, the presence of current depressive and/or anxiety disorders was associated with lower cotinine levels, which may point to a different smoking topography or a faster cotinine metabolism in individuals with affective disorders. The latter could help to explain the higher number of cigarettes smoked and poorer cessation rates among depressed or anxious patients. © 2014 S. Karger AG, Basel.European Addiction Research 01/2014; 20(4):183-191. DOI:10.1159/000356809 · 2.07 Impact Factor
Article: Genetics and Smoking[Show abstract] [Hide abstract]
ABSTRACT: Regular smoking is the major risk factor for cardiovascular disease and cancers, and thus is one of the most preventable causes of morbidity and mortality worldwide. Intake of nicotine, its central nervous system effects, and its metabolism are regulated by biological pathways; some of these are well known, but others are not. Genetic studies offer a method for developing insights into the genes contributing to those pathways. In recent years, large genome-wide association study (GWAS) meta-analyses have consistently revealed that the strongest genetic contribution to smoking-related traits comes from variation in the nicotinic receptor subunit genes. Many other genes, including those coding for enzymes involved in nicotine metabolism, also have been implicated. However, the proportion of phenotypic variance explained by the identified genetic variants is very modest. This review intends to cover progress made in genetics and genetic epidemiology of smoking behavior in recent years, and focuses on studies revealing the nicotinic receptor gene cluster on chromosome 15q25. Evidence supporting the involvement of a novel pathway in the shared pathophysiology of nicotine dependence and schizophrenia is also briefly reviewed. A summary of the current knowledge on gene–environment interactions involved in smoking behavior is included.03/2014; 1(1). DOI:10.1007/s40429-013-0006-3
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ABSTRACT: Nicotine metabolism influences smoking behavior and differences in metabolism likely contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by CYP2A6-catalyzed C-oxidation, UGT2B10-catalyzed N-glucuronidation and FMO3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n=364), Native Hawaiian (NH, n=311), White (n=437), Latino (LA, n=453) and Japanese American (JA, n=674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; least-square means were computed and adjusted for age, sex, creatinine, and BMI. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (p<0.0001), and N-glucuronidation lowest in AA (p<0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2 and 3-fold lower in AA compared to Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (p=0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.Carcinogenesis 09/2014; DOI:10.1093/carcin/bgu191 · 5.27 Impact Factor