Populations of Black-African descent have slower rates of nicotine and cotinine metabolism, smoke fewer cigarettes (~10 cigarettes/day), and have higher incidences of tobacco-related illnesses compared to Caucasians. Cytochrome P450 2A6 (CYP2A6) is the main enzyme involved in the metabolism of nicotine and its proximal metabolite cotinine, as well as tobacco-specific nitrosamines. Genetic polymorphisms in CYP2A6 contribute to the large variability observed in rates of nicotine metabolism. Reduced CYP2A6 activity has been associated with fewer cigarettes smoked, higher quit rates, and lower lung cancer risk in predominantly moderate to heavy-smoking (~20–30 cigarettes/day) Caucasians. CYP2A6 genetic variants and their impact on smoking behaviours have not been well studied among individuals of Black-African descent. The main objectives herein were to identify and characterize new CYP2A6 variants that may explain the slower rates of metabolism, and determine whether CYP2A6 variation is a predictor of smoking phenotypes in this population. Furthermore, we examined whether previously validated biomarkers of tobacco exposure have limitations among individuals of Black-African descent given their low and sporadic smoking patterns. A new CYP2A6 variant (CYP2A6*23) was found in individuals of Black-African descent recruited for a nicotine pharmacogenetic-pharmacokinetic study. CYP2A6*23 reduced activity towards nicotine and coumarin in vitro and was associated with slower rates of CYP2A6 kinetics in vivo. In a clinical trial of African-American light smokers, CYP2A6 slow metabolizers were more successful at smoking cessation compared to normal metabolizers, although no differences in cigarette consumption were found. Two common biochemical markers of tobacco smoke exposure, cotinine and exhaled carbon monoxide, were weakly correlated with self-reported cigarette consumption. These biomarkers were not substantially affected by variables previously shown to alter amount smoked and/or rates of cotinine metabolism such as gender, age, body mass index or smoking menthol cigarettes. However, CYP2A6 slow metabolizers had significantly higher cotinine without smoking more cigarettes. Identification and characterization of novel variants adds to our understanding of nicotine pharmacokinetic differences between racial/ethnic minority groups and improves accuracy of CYP2A6 genotype groupings for genetic association studies. Furthermore, better insight into the biological factors associated with smoking behaviours will aid in the development of more efficacious targeted treatments for this understudied population.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/29746 |
| Date | 30 August 2011 |
| Creators | Ho, Man Ki |
| Contributors | Tyndale, Rachel |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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