Smoking, nicotine metabolism and cytochromes P450:  Impact of genetic and regulatory variation.
Published: 2004
Language: eng
Number of pages: 314
Description: Variation in nicotine metabolism and cytochromes P450 (CYPs) may alter smoking risk and behaviour. Sources of regulatory variation in CYP2A (and CYP2B) and nicotine metabolism were examined in animal models, and the impact of genetic variation in CYP2A6 on smoking risk and behaviour in humans was determined. A rat model was used to determine the effect of chronic ethanol treatment on nicotine metabolism and CYP2B1/2 in rat brain and liver. Ethanol did not alter CYP2B1/2 protein in 6 brain regions; however a dose-dependent induction of CYP2B1/2 mRNA, protein and in vitro nicotine metabolism, was detected in the liver. In order to evaluate the effects of chronic nicotine on hepatic levels of CYP2A6 and CYP2B6 and nicotine metabolism, an African green monkey (AGM) model was developed. Significant decreases in hepatic CYP2A protein and mRNA as well as in vitro and CYP2A-mediated nicotine metabolism were observed in AGM. An epidemiological study was then conducted in order to determine the impact of genetic variation in  CYP2A6 on smoking risk and behaviour. CYP2A6 allele frequencies varied significantly by ethnicity. Adult Caucasian non-smokers (N = 224) (10--99 cigarettes/lifetime) and current, regular smokers (N = 375) (>100 cigarettes/lifetime) completed questionnaires assessing demographics, tobacco and drug use history and were genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2,  CYP2A6*4, CYP2A6*9, CYP2A6*12). The proportion of individuals with slow inactivator genotypes was significantly different between the non smokers (12.5%) and regular smokers (6.9%) (p = 0.027, OR = 0.52 [95% CL; 0.30--0.91]). A similar finding was observed when regular smokers included only those meeting DSM-IV criteria for nicotine dependence (N = 315). Among regular, dependent smokers, mean daily cigarette consumption was significantly (P = 0.003) lower for individuals with slow inactivator genotypes (21.3 cigarettes/day [95% CL; 17.4--25.2]) compared to the normal inactivators (28.2 cigarettes/day [95% CL; 26.4--29.9]). Slow inactivators also had a significantly (p = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age [95% CL; 12.1--14.0] versus 14.2 [95% CL; 13.8--14.6]. These studies identified several sources of regulatory variation in nicotine metabolism using animal models and demonstrated the impact of genetic variation in nicotine-metabolizing CYP2A6 on smoking behaviour in humans.
Notes: Adviser:  Rachel F. Tyndale.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5099.