Item – Theses Canada

OCLC number
Howard, Lisa Angela,1975-
Alcohol, nicotine and genetic variation influence CYP2E1.
Ph. D. -- University of Toronto, 2003
Ottawa :National Library of Canada = Bibliothèque nationale du Canada,[2004]
4 microfiches.
Includes bibliographical references.
CYP2E1 inactivates alcohol to acetate and it bioactivates several procarcinogens and protoxins. Most alcoholics smoke cigarettes. Smoking may decrease the duration of alcohol's effects by increasing its metabolism, providing a stimulus for increased alcohol consumption. Nicotine, the pharmacologically-active tobacco smoke constituent that establishes and maintains tobacco dependence, was hypothesized to induce hepatic CYP2E1. CYP2E1 was significantly increased by low doses of nicotine in the centrilobular region of liver in rats, as it was by ethanol, an established hepatic CYP2E1 inducer. Region- and cell-specific induction of brain CYP2E1 in rats exposed to either of these psychoactive drugs was also observed. Moreover, greater CYP2E1 levels were found in human brain regions of smoking and non-smoking alcoholics compared to non-smoking non-alcoholics. Subsequently, the influence of the greater inducibility variant 'CYP2E1*1D' on being alcohol dependent was investigated in individuals who were, and were not, nicotine dependent. In this epidemiology study (N = 1500) 15-fold variation was found among the 8 ethnic groups studied in the frequency of 'CYP2E1*1D'. As hypothesized, a significant association between 'CYP2E1*1D' and alcohol dependence was observed among Canadian Native Indians. Interestingly, ' CYP2E1*1D' was also associated with nicotine dependence among Canadian Native Indians and Japanese participants. The examination of this ' CYP2E1' polymorphism with markers of nicotine metabolism suggested that African Americans who had at least one 'CYP2E1*1D' allele had greater levels of a secondary nicotine metabolite, 3-hydroxy-cotinine. A case-control study of the influence of 'CYP2E1*1D' on smoking and lung cancer risk was then performed. Caucasians who had at least one ' CYP2EI*1D' allele had a significant 3.5-fold greater risk of being a smoker. However, 'CYP2E1*1D' was not found to substantially influence overall lung cancer risk in this study. Collectively, these findings suggest that nicotine-induced CYP2E1 may have a role in the development of metabolic cross-tolerance of alcohol and nicotine as well as in CYP2E1-generated toxicity. These observations also indicate that genetic variation in ' CYP2E1' inducibility may contribute to inter-ethnic and inter-individual differences in the risk to become alcohol and nicotine dependent. This may influence the risk to develop alcohol and tobacco-related diseases in certain individuals or ethnic groups.