Nicotine is the primary substance in tobacco causing addiction. In humans the majority (70-80%) of nicotine is inactivated to cotinine in a reaction predominantly catalyzed by CYP2A6 (80-90%), with a minor possible role for CYP2B6. Substantial interindividual variability is observed in the rate of nicotine’s inactivation to cotinine and this variation contributes to differences in smoking behaviors (e.g. cigarette consumption). Twin studies suggest an important genetic contribution to the variability in nicotine metabolism. However in 2004, genetic variation in CYP2A6 and CYP2B6 accounted for only a small portion of the variability suggesting gaps in our knowledge. Our objective was to identify additional genetic and non-genetic sources of variability in CYP2A6 expression/activity, CYP2B6 expression, and nicotine to cotinine metabolism in vivo and/or in vitro. Participants included individuals from different world populations phenotyped for CYP2A6 activity either following oral nicotine administration or using metabolite ratios derived from baseline smoking. Genotyping and sequencing were utilized to identify and characterize multiple new CYP2A6 alleles. In total 17 novel CYP2A6 alleles were identified, many of which were found predominantly among individuals of black African descent and exhibited lower CYP2A6 activity. In addition, human livers were assessed for CYP2A6 and CYP2B6 expression and nicotine to cotinine metabolism. The mechanisms underlying the lower CYP2A6 activity associated with some of the variant CYP2A6 alleles included either a reduction in hepatic CYP2A6 protein expression, an alteration of CYP2A6’s structural property, or a combination of both. DNA methylation was not associated with altered hepatic CYP2A6 expression/activity. Livers from female donors were associated with higher CYP2A6 and CYP2B6 protein expression compared to male livers, while age did not influence the expression of either CYP. Finally, CYP2B6 and its prevalent altered function genetic variant (CYP2B6*6) did not influence nicotine to cotinine metabolism. Identification of factors that contribute to the variability in CYP2A6 and nicotine metabolism is important to improve future association studies between CYP2A6 genotype, nicotine metabolism, and smoking behaviors. In addition, this information could provide the potential to personalize therapy in order to improve the clinical efficacy of nicotine, particularly as a smoking cessation aid.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/25920 |
| Date | 14 January 2011 |
| Creators | Al Koudsi, Nael |
| Contributors | Tyndale, Rachel |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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