Rachel F. Tyndale

Nicotine metabolism defect reduces smoking

Nicotine is the primary compound in tobacco that establishes and maintains tobacco dependence. Most of this nicotine is metabolized to cotinine by the genetically variable enzyme CYP2A6. Here we show that individuals lacking full functional CYP2A6, who therefore have impaired nicotine metabolism, are significantly protected against becoming tobacco-dependent smokers. In addition, smokers whose nicotine metabolism is thus impaired smoke significantly fewer cigarettes than those with normal nicotine metabolism.

Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians.

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Adult Caucasian non-smokers (n = 224) (1-99 cigarettes/lifetime) and smokers (n = 375) (> or = 100 cigarettes/lifetime) were assessed for demographics, tobacco/drug use history and DSM-IV dependence and genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). CYP2A6 allele frequencies varied substantially among the ethnic groups. The proportion of Caucasian slow nicotine inactivators was significantly lower in current, DSM-IV dependent smokers compared to non-smokers [7.0% and 12.5%, respectively, P = 0.03, odds ratio (OR) = 0.52; 95% confidence interval (CI) 0.29-0.95]; non-dependent smokers showed similar results. Daily cigarette consumption (cigarettes/day) was significantly (P = 0.003) lower for slow (21.3; 95% CI 17.4-25.2) compared to normal inactivators (28.2; 95% CI 26.4-29.9); this was observed only in DSM-IV dependent smokers. Slow inactivators had a significantly (P = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age; 95% CI 12.1-14.0 versus 14.2; 95% CI 13.8-14.6), and a trend towards smoking for a shorter duration. This study demonstrates that slow nicotine inactivators are less likely to be adult smokers (dependent or non-dependent). Slow inactivators also smoked fewer cigarettes per day and had an earlier age of first smoking (only dependent smokers).

Implications of CYP2A6 Genetic Variation for Smoking Behaviors and Nicotine Dependence

Nicotine is the primary addictive compound in tobacco smoke. In this review we summarize nicotine dependence and the genetics of smoking in brief before focusing on cytochrome P450 (CYP) 2A6. In humans nicotine is mainly inactivated to cotinine and CYP2A6 mediates approximately 90% of this conversion. Some, but not all, studies suggest that genetic variation in CYP2A6 may play a role in smoking. We review some of the recent findings on the influence of CYP2A6 genetic polymorphisms on nicotine kinetics, smoking behaviors, and how the gene appears to exert differential effects during various stages of smoking (eg, initiation, conversion to dependence, amount smoked during dependence, and quitting). These new findings will be put in the context of the discrepancies found in the literature. Implications of these recent findings on current and novel treatment approaches for smoking cessation and tobacco‐related lung cancer will also be discussed.

Genetics of alcohol and tobacco use in humans

The field of genetics holds great promise for furthering our understanding of the etiology of drug dependence and for identifying novel targets for treatment. Genetic studies utilizing twins and families have demonstrated a considerable role for genetics in nicotine and/or alcohol dependence. Risk for alcoholism or nicotine dependence is likely to be the result of a large number of genes, each contributing a small fraction of the overall risk. While this review will focus on studies in humans, many of the candidate genes for human nicotine and alcohol dependence listed here were originally postulated to be important, based on data from animal studies. The review will briefly summarize the results from twin and adoption studies that provide estimations of heritability, the results from chromosomal linkage studies that identify regions of chromosomes that may contain relevant genes, and the results of candidate gene studies. For each topic the data will be presented for nicotine dependence, alcohol dependence, and for nicotine and alcohol dependence together. In addition, each section will review briefly some of the confounding issues in the specific type of approach utilized.

Nicotine-dependence symptoms are associated with smoking frequency in adolescents

BACKGROUND Although many sociodemographic and psychosocial factors have been identified as related to adolescent smoking, few studies have examined the role of nicotine-dependence (ND) symptoms. The objective was to study the association between ND symptoms and smoking status among adolescents in the early stages of the smoking onset process. METHODS The McGill University Study on the Natural History of Nicotine Dependence is an ongoing 6-year prospective investigation of the natural history of ND among 1267 grade 7 students in ten Montreal high schools. The baseline response was 55.4%. Subjects for this cross-sectional analysis of baseline data, collected in 1999, included 241 past 3-month smokers (mean age [SD]=13.0+/-0.7 years at baseline). ND symptoms were measured in five indicators, including a measure based on the criteria for tobacco dependence in the International Classification of Diseases-10th Revision (ICD-10), the Hooked on Nicotine Checklist, and three symptom clusters (withdrawal, self-medication, and ND/cravings symptoms). The association between ND symptom indicators and each of sporadic, monthly, weekly, and daily smoking relative to less frequent smoking was investigated in multiple logistic regression analysis. RESULTS Despite low cigarette exposure, 16.6% (95% confidence interval [CI], 11.9%-21.3%) of past 3-month smokers were tobacco dependent. The proportion increased from 0%, 3.1% (95% CI, 0.0%-9.2%), and 4.6% (95% CI, 0.2%-9.0%) among triers, sporadic smokers, and monthly smokers, respectively, to 19.4% (95% CI, 5.5%-33.3%) and 65.9% (95% CI, 51.9%-79.9%) among weekly and daily smokers, respectively. ND/cravings consistently distinguished each smoking category from less frequent smokers; the odds ratios (95% CI) for ND/cravings symptoms were 1.16 (0.99-1.35) in sporadic smokers; 1.17 (1.06-1.29) in monthly smokers; 1.34 (1.19-1.50) in weekly smokers; and 1.39 (1.22-1.59) in daily smokers. CONCLUSIONS These data challenge current smoking onset models, which suggest that ND develops only after several years of heavy or daily smoking. ND symptoms are associated, at least cross-sectionally, with increased smoking in adolescents. To increase the likelihood of being effective, tobacco-control programs for children and adolescents will need to take early ND symptoms into account.

The Pharmacogenetics Research Network: From SNP Discovery to Clinical Drug Response

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug‐metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation

Nicotine is metabolized to cotinine, and cotinine is metabolized to 3′‐hydroxycotinine (3‐HC) by the liver enzyme cytochrome P450 (CYP) 2A6. More rapid metabolism of nicotine may result in lower nicotine blood levels from nicotine replacement products and poorer smoking cessation outcomes. This study evaluated the utility of the 3‐HC/cotinine ratio as a predictor of the efficacy of nicotine replacement therapy as an aid for smoking cessation.

Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain.

CYP2B6 metabolizes drugs such as nicotine and bupropion, and many toxins and carcinogens. Nicotine induces CYP2B1 in rat brain and in humans polymorphic variation in CYP2B6 affects smoking cessation rates. The aim of this study was to compare CYP2B6 expression in brains of human smokers and non-smokers and alcoholics and non-alcoholics (n=26). CYP2B6 expression was brain region-specific, and was observed in both neurons and astrocytes. CYP2B6 levels were higher in brains of smokers and alcoholics, particularly in cerebellar Purkinje cells and hippocampal pyramidal neurons, cells known to be damaged in alcoholics. Significantly more (p<0.05) CYP2B6 protein was seen in four brain regions of smoking alcoholics compared to non-smoking non-alcoholics: hippocampus (5.8-fold), caudate nucleus (3.3-fold), putamen (3.0-fold) and cerebellar hemisphere (1.6-fold). The genetic variant C1459T (R487C) has been associated with reduced hepatic enzyme levels, stability and activity. Preliminary genotyping of this small sample (n=24) suggested that individuals with the CC genotype had higher brain CYP2B6 than those with the CT or TT genotype. Higher brain CYP2B6 activity in smokers and alcoholics may cause altered sensitivity to centrally acting drugs, increased susceptibility to neurotoxins and carcinogenic xenobiotics and contribute to central tolerance to nicotine.

Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy

We investigated the effect of slow metabolism of nicotine, predicted by CYP2A6 genotypes resulting in ⩽50% activity, on baseline smoking behaviours and treatment variables in an open-label nicotine replacement therapy (NRT) clinical trial. Caucasian smokers with CYP2A6 slow vs normal metabolism had lower metabolic activity, indicated by the 3-hydroxycotinine/cotinine ratio (0.23±0.17 vs 0.45±0.22, P<0.01, respectively). CYP2A6 slow metabolizers also smoked fewer cigarettes per day compared to normal metabolizers (20±7 vs 24±10, respectively, P<0.04). With nicotine patch use, slow metabolizers had higher nicotine plasma levels compared to normal metabolizers (22.8±4.6 vs 15.8±7.6 ng/ml, respectively, P=0.02) while using the same numbers of patches/week. With nicotine spray use, where like in smoking the nicotine intake can be easily adjusted to adapt to rates of metabolism, slow metabolizers achieved similar nicotine levels compared to normal metabolizers (5.8±4.1 vs 8.0±9.1 ng/ml, P=0.82), by using fewer doses of nicotine spray/day (4.8±3.6 vs 10.5±8.0, respectively, P<0.02). These findings indicate that CYP2A6 genotype influences smoking behaviour in a Caucasian treatment-seeking population and that CYP2A6 genotype affects plasma levels obtained from, and usage of, NRT.

CYP2A6 genotype and the metabolism and disposition kinetics of nicotine.

The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously.