Full length articleCessation of alcohol consumption decreases rate of nicotine metabolism in male alcohol-dependent smokers
Introduction
Cigarette smoking and excessive alcohol consumption remain two of the leading preventable causes of premature death in the U.S. and around the world (Danaei et al., 2009). These are highly co-morbid behaviors and the prevalence of cigarette smoking in individuals with alcohol use disorders is high (see McKee and Weinberger, 2013 for review). Results from a national sample found the prevalence of any alcohol use disorders was higher among individuals with nicotine dependence compared to the overall population (22.8% vs 8.5%; Grant et al., 2004); and around half of all adults in the US with an alcohol use disorder also smoke cigarettes (McKee and Weinberger, 2013). Individuals with alcohol use disorders have also been found to be heavier smokers, report greater nicotine dependence, and have poorer smoking cessation rates (Burling et al., 1997, Cook et al., 2012, Friend and Pagano, 2005, Keenan et al., 1990, Hughes and Kalman, 2006, Hurt et al., 1995, John et al., 2003a, John et al., 2003b, Marks et al., 1997, York and Hirsch, 1995).
Underlying factors that contribute to the differences in prevalence of cigarette smoking and nicotine dependence among individuals with alcohol use disorders remain unclear. Research has largely focused on the hypothesis that nicotine and alcohol in combination may have combined pharmacological effects that support their co-use (e.g., increased reward and/or decreased withdrawal/aversive effects). An additional mechanism that could contribute to this difference in cigarette smoking behavior and dependence in this population is a change in the pharmacokinetics of nicotine induced by chronic alcohol consumption.
Nicotine is primarily metabolized into cotinine by the liver enzyme CYP2A6 (C-oxidation), which accounts for approximately 75% of nicotine metabolism (Benowitz et al., 2009). Cotinine is further metabolized to trans-3′-hydroxycotine (3HC) in a process mediated exclusively or nearly exclusively by the same enzyme, CYP2A6. The ratio of 3HC/cotinine, termed the nicotine metabolite ratio (NMR) is a validated biomarker for CYP2A6 activity and the rate of nicotine metabolism (Dempsey et al., 2004). A higher NMR indicates greater CYP2A6 enzyme activity and faster rate of nicotine metabolism.
In addition to cotinine and 3HC, nicotine is metabolized to a number of other metabolites via the CYP2A6 and other metabolic pathways (see Benowitz et al., 2009 for review). In the current study we also assessed a number of different metabolites of nicotine in addition to products from the C-oxidation pathway. For example nicotine is also metabolized by glucuronidation (primarily by UDP glucuronosyltransferase 2 family, polypeptide B10; UGT2B10) and N-oxidation (by flavin containing monooxygenase 3; FMO3), although these pathways contribute less to the overall metabolism of nicotine compared to CYP2A6 (Hukkanen et al., 2005). If metabolism of nicotine via the C-oxidation pathway is slower, higher levels of non-C-oxidation products (e.g., nicotine glucuronide and nicotine-N-oxide) would be expected.
A faster rate of nicotine metabolism (greater CYP2A6 enzyme activity) was previously found to be associated with smoking more cigarettes per day (Benowitz et al., 2003, Strasser et al., 2011, Tanner et al., 2015), greater nicotine withdrawal symptoms (Rubinstein et al., 2008, Sofuoglu et al., 2012), and decreased efficacy of nicotine replacement therapy (NRT) for smoking cessation (Lerman et al., 2006, Lerman et al., 2015). Tobacco use characteristics associated with faster rate of nicotine metabolism are similar to what has been found in individuals with alcohol use disorders, as previously discussed. Both genetic (Ray et al., 2009) and environmental factors have been found to influence CYP2A6 enzyme activity. For example estrogen (Benowitz et al., 2006, Dempsey et al., 2002), and certain medications such as phenobarbital (Benowitz et al., 2009) and rifampicin (Xia et al., 2002) have been found to induce CYP2A6 enzyme activity, resulting in accelerated rate of nicotine metabolism.
Previous research suggests that chronic alcohol may induce CYP2A6 enzyme activity. Protein levels of CYP2A6 were found to be higher among patients who abuse alcohol (Niemelä et al., 2000) and alcohol was found to induce CYP2A6 activity in the U937 macrophage cell line (Jin et al., 2011, Jin et al., 2012). In mice chronic alcohol consumption induced CYP2A5, the mouse orthologue of human CYP2A6 (Lu et al., 2011, Lu et al., 2012). The current study examined the hypothesis that chronic alcohol abuse accelerates the rate of nicotine metabolism and is associated with higher NMR and altered patterns of nicotine metabolism. We examined this hypothesis by looking at reversal of postulated metabolic induction after cessation of alcohol abuse, testing subjects at three time points over the course of 7 weeks of inpatient treatment for alcohol dependence. It was hypothesized that rate of nicotine metabolism assessed by NMR would decrease over the 7 weeks of alcohol abstinence, reflecting normalization after prior enzyme induction.
Total Nicotine Equivalents (TNE), the molar sum of nicotine and its metabolites measured in urine, is a highly reliable biomarker of total nicotine exposure (Scherer et al., 2007) that is unaffected by differences in CYP2A6 enzyme activity (Benowitz et al., 2010, Derby et al., 2008, Feng et al., 2007). TNE was used to determine if there was a change in nicotine exposure at the three assessments after alcohol cessation. In addition, biomarkers of liver function were also assessed to verify subjects did not have severe liver function impairments and to verify that the expected decrease in these liver function metabolites occurred after cessation of alcohol.
Understanding changes in nicotine metabolism associated with chronic alcohol abuse and recovery (during alcohol abstinence) could have important implications for understanding smoking behavior and improving smoking cessation interventions for current and former heavy alcohol drinkers.
Section snippets
Setting
The study was conducted from September 2011 to May 2012 at the Center for Addiction Treatment (Ośrodek Terapii Uzależnień, OTU), an inpatient program dedicated to the treatment of alcohol dependence located in Parzymiechy, Poland. The center treats approximately 1200 individuals per year for alcohol dependence with an average treatment duration per patient of 8 weeks. Patients entering the program were first treated for acute alcohol withdrawal for up to 2 weeks in an alcohol detoxification
Baseline characteristics
The baseline demographic, smoking, and alcohol drinking variables for the entire group of male and female smokers who completed the study (n = 165) are shown in Table 1. As discussed in methods, 22 male individuals were randomly selected for analysis of nicotine metabolites. Shown in Table 1 is a comparison of the subsample that was included in the metabolite assay compared to the overall sample population. The subsample and overall sample were comparable with the exception of a slightly higher
Discussion
The present study among male Caucasians is to the best of our knowledge the first to demonstrate that in alcohol dependent cigarette smokers the cessation of alcohol consumption results in a significant and substantial decrease in the rate of nicotine metabolism (lower NMR). This is consistent with previous work suggesting that chronic alcohol consumption may induce CYP2A6, the enzyme primarily responsible for the metabolism of nicotine. CYP2A6 protein levels were found to be elevated in the
Role of funding source
The study was funded by grant N404 145539 from the Ministry of Science and Higher Education of Poland. Nicotine biomarker analysis was support by NIH (NIDA DA02277 and P30 DA012393). The preparation of this manuscript was supported by NIH NCI CA-113710. The funding sources had no involvement in the study design, in the collection, analysis and interpretation of the data, in the writing of the report, or in the decision to submit the article for publication.
Contributions
N.R.G, N.L.B and M.L.G. wrote the manuscript. M.L.G and A.S designed the research. A.K-K., I.S-B., E.S-M., J.G. and M.L.G. performed the research and data collection. P.J. III supervised the laboratory analyses of nicotine metabolites. N.R.G, N.L.B, and M.L.G. analyzed the data. All authors read and approved the final manuscript.
Conflict of interest
AS received personal fees from the Smoking Institute in Poznan, Poland, and nonfinancial support from Chic Group LTD, a manufacturer of electronic cigarettes in Poland, outside of the submitted work. MLG received a research grant from Pfizer Inc., a manufacturer of smoking cessation medications. NLB serves as a paid consultant to pharmaceutical companies that are developing or that market smoking cessation medications. He also has been a paid expert witness in litigation against tobacco
Acknowledgments
We thank Faith Allen for data management and Trisha Mao, Lisa Yu and Lawrence Chan for analytical chemistry.
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