CYP2E1  1D regulatory polymorphism: association with alcohol and nicotine dependence Lisa A. Howard a , Jasjit S. Ahluwalia b , Shih-Ku Lin c , Edward M. Sellers a,d,e and Rachel F. Tyndale a,e Objective CYP2E1 bioactivates environmental protoxins and metabolizes alcohol. CYP2E1 is induced by alcohol and cigarette smoking and may contribute to metabolic tolerance in alcoholics. The CYP2E1  1D polymorphism has been associated with greater CYP2E1 inducibility. One objective was to determine the frequency of the variant allele in eight ethnic groups. Further, the Canadian Native Indian, South-east Asian Canadian and Caucasian Canadian groups were stratified by alcohol and nicotine dependence (as measured by DSM-IV criteria) to examine the potential association of CYP2E1  1D with drug dependence. Results and conclusions We found a significantly greater frequency of the CYP2E1  1D allele among Indo-Asian Canadians (0.31), Chinese Canadians (0.19), Taiwanese (0.20), Japanese Canadians (0.18), African Americans (0.13), African Canadians (0.10) and Canadian Native Indians (0.09) compared to Caucasian Canadians (0.02). Although the power of the association study was low among some subgroups, the CYP2E1  1D genotype (subjects with at least one variant allele) was associated with alcohol as well as nicotine dependence. Specifically, Canadian Native Indians dependent on nicotine alone or alcohol alone exhibited significantly greater CYP2E1  1D frequencies compared to non-drug dependent controls, while the variant frequency among Southeast Asians dependent on nicotine was greater than their non-drug dependent counterparts. We also found that CYP2E1  1D genotype was associated with significantly greater 3- hydroxycotinine per cigarette in African Americans. The variable frequency of CYP2E1  1D among ethnic groups suggests a greater risk for diseases putatively related to CYP2E1 in some non-Caucasian ethnic groups. The association of CYP2E1  1D with alcohol and nicotine dependence suggests that CYP2E1 may contribute to the development of these dependencies. Pharmacogenetics 13:321–328 & 2003 Lippincott Williams & Wilkins Pharmacogenetics 2003, 13:321–328 Keywords: CYP2E1, alcohol, nicotine, dependence, smokers, alcoholics, polymorphism a Departments of Pharmacology and d Medicine and Psychiatry, University of Toronto, Toronto, Ontario, Canada, b Department of Preventive Medicine and Public Health, University of Kansas Medical Center, Kansas City, Missouri, USA, c Department of Addiction Science, Taipei City Psychiatric Center, Taipei, Taiwan, and e Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Corresponding author: Dr RF Tyndale, Department of Pharmacology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada, M5S 1A8. Tel: +1 416 978 6374; fax: +1 416 978 6395; e-mail: r.tyndale@utoronto.ca Received 16 January 2003 Accepted 21 March 2003 Introduction The cytochrome P450 2E1 (CYP2E1) enzyme can metabolize numerous xenobiotics, such as alcohol and tobacco smoke nitrosamines, converting them to reac- tive metabolites [1]. In addition, under conditions that induce CYP2E1, the enzyme has a high capability to generate reactive oxygen species and substrate-derived radicals which can mediate lipid peroxidation, protein inactivation and DNA damage [2]. Inter-ethnic varia- tion in CYP2E1 enzyme activity may contribute to the disparity in responsiveness to drugs, biotransformation of drugs, and susceptibility to xenobiotic-induced dis- eases between ethnic groups [3,4]. For example, Afri- can Americans have a higher risk of alcohol-related diseases (e.g. fetal alcohol syndrome) as well as tobac- co-related conditions (e.g. lung and hepatocellular can- cers) compared to Caucasians [5–8]. At high concentrations, CYP2E1 oxidizes alcohol to acetaldehyde and then acetaldehyde to acetate [3,9]. CYP2E1 is induced by chronic alcohol intake and contributes to the increased alcohol metabolism ob- served in alcoholic drinkers [10,11]. An estimated 80– 95% of alcoholic drinkers smoke regularly [12]. The co- abuse of alcohol and tobacco could involve the develop- ment of metabolic tolerance to one agent after chronic exposure to the other, in addition to pharmacodynamic interactions [13]. For instance, studies have shown that compared to non-smokers, smokers have higher alcohol elimination rates [14] and greater CYP2E1 activity [15,16], although some other studies do not agree [17,18]. These differences in findings may be due to variable smoking levels among study participants, the Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. This work was funded in part by CIHR grant MOP 53248 and MT 14173 and the Centre for Addiction and Mental Health. We also acknowledge the support of a Canadian Institutes of Health Research and Natural Science and Engineering Research Council of Canada scholarships to L.A.H. and a Canadian Research Chair in Pharmacogenetics to R.F.T. Original article 321 0960-314X & 2003 Lippincott Williams & Wilkins DOI: 10.1097/01.fpc.0000054090.48725.a2