ABSTRACT
BACKGROUND: Variability in smoking behavior is partly attributable to heritable individual differences in nicotine clearance rates. This can be assessed as the ratio of the metabolites cotinine and 3'-hydroxycotinine (referred to as the nicotine metabolism ratio; NMR). We hypothesized that faster NMR would be associated with greater cigarette puff volume and higher levels of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a carcinogen biomarker. METHODS: Current smokers (n = 109) smoked one of their preferred brand cigarettes through a smoking topography device and provided specimens for NMR and total NNAL assays. RESULTS: Faster nicotine metabolizers (third and fourth quartiles versus first quartile) based on the NMR exhibited significantly greater total puff volume and total NNAL; the total puff volume by daily cigarette consumption interaction was a significant predictor of total NNAL level. CONCLUSION: A heritable biomarker of nicotine clearance predicts total cigarette puff volume and total NNAL. IMPACT: If validated, the NMR could contribute to smoking risk assessment in epidemiologic studies and potentially in clinical practice.
Subject(s)
Cotinine/analogs & derivatives , Cotinine/blood , Nicotine/pharmacokinetics , Nitrosamines/urine , Pyridines/urine , Smoking/metabolism , Adolescent , Adult , Aged , Aryl Hydrocarbon Hydroxylases/genetics , Biomarkers/blood , Biomarkers/urine , Cytochrome P-450 CYP2A6 , Female , Genotype , Humans , Male , Middle Aged , Prognosis , Risk Assessment , Smoking/genetics , Survival Rate , Young AdultABSTRACT
This article reviews evidence supporting the potential utility of a pharmacogenetic approach to the treatment of nicotine dependence. There is substantial evidence that nicotine dependence and smoking persistence are heritable, and are determined by a complex interplay of polygenic and environmental influences. The most robust evidence for specific genetic influences on nicotine dependence is found in studies of genetic variation in nicotine-metabolizing enzymes. Data also support the role of genes in the dopamine and opioid pathways as predictors of dependence and smoking relapse; however, the evidence for genetic associations is not always consistent. Emerging data from pharmacogenetic trials of nicotine-dependence treatment are promising, suggesting that genetic profiles of smokers someday may be used by providers to choose the type, dose, and duration of treatment for individual smokers. However, additional trials including larger and more diverse populations are needed before such data can be translated to practice to reduce smoking prevalence and tobacco-related disease.
Subject(s)
Pharmacogenetics/methods , Smoking Cessation/methods , Tobacco Use Disorder/genetics , Tobacco Use Disorder/rehabilitation , Bupropion/pharmacokinetics , Bupropion/therapeutic use , Controlled Clinical Trials as Topic , Dopamine Uptake Inhibitors/pharmacokinetics , Dopamine Uptake Inhibitors/therapeutic use , Humans , Nicotine/administration & dosage , Nicotine/metabolism , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/metabolism , Smoking/genetics , Smoking Prevention , Treatment OutcomeABSTRACT
The authors review recent advances in the pharmacotherapy and pharmacogenetics of nicotine dependence. Despite the negative health consequences of smoking, approximately 23% of adults in the United States are daily tobacco smokers and approximately 13% are nicotine dependent. Data for development of new medications for nicotine dependence are likely to come from animal models of the reinforcing value of nicotine, studies to identify proteins in transgenic rodents, and pharmacological studies of nicotine withdrawal. The initial pharmacogenetic studies of pharmacotherapies approved by the United States Food and Drug Administration for treatment of nicotine dependence-nicotine replacement (nicotine gum, nicotine nasal spray, and transdermal nicotine) and bupropion-have identified candidate alleles at the dopamine D2 receptor gene and mu opioid receptor gene that may predict therapeutic response. Because no one medication is likely to be safe and efficacious for a majority of persons with nicotine dependence, it will be useful to develop genetics-based methods and other tools to predict therapeutic response in subgroups of nicotine-dependent persons.
