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Professor, Pharmacology
Canada Research Chair in Pharmacogenetics
Section Head Pharmacogenetics
Centre for Addiction and Mental Health
General Area of Research: Molecular Pharmacology, Genetics and Toxicology; Drug Metabolism
and Neuropharmacology Genetic And Environmental Factors which Influence Drug Dependence |
The cytochromes P450 (CYP) enzyme system is involved in the activation and inactivation of drugs. Genetic defects in these genes can alter drug metabolism and create interindividual differences in drug efficacy, toxicity and drug dependence. We investigate these interindividual differences using molecular genetic, pharmacogenetic and pharmacokinetic approaches, using in vitro, animal, epidemiological and clinical treatment studies. In addition, CYPs are present in the central nervous system where they are regulated by drugs of abuse (e.g., alcohol and nicotine). We investigate the influences of drugs of abuse on brain CYPs, integrating the fields of drug metabolism and receptor neuropharmacology, in order to identify interindividual differences in neurotoxicity and drug response. Our experimental approach principally involves biochemical, protein and molecular biological techniques.
Selected Publications:
JC Mwenifumbo, N Al Koudsi, EB Hoffmann, Q Zhou, MK Ho, EM Sellers and RF Tyndale. Novel and established CYP2A6 alleles alter in vivo nicotine metabolism in a population of black African descent. Human Mutation. 2008, in press
MK Ho, JC Mwenifumbo, Z Bin, RF Tyndale. A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black African descent. Pharmacogenetics and Genomics, 2008; 18:67-75.
J Yue, S Miksys, E Hoffmann, RF Tyndale. Chronic nicotine treatment induces rat CYP2D in brain but not in liver: an investigation of induction and time course. J Psychiat. and Neurosci. 2008; 33(1):54-63.
ECK Siu and RF Tyndale. Selegiline (L-deprenyl) is a mechanism-based inactivator of CYP2A6 inhibiting nicotine metabolism in humans and mice. J Pharmacol. and Exp. Ther. 2007 Dec 7; [Epub ahead of print]
AM Lee, C Jepson, E Hoffmann, L Epstein, LW Hawk, C Lerman, RF Tyndale CYP2B6 genotype alters abstinence rates for smoking cessation treatment. Biol. Psychiat. 2007; 15;62(6):635-41.
J Audrain-McGovern, N Al Koudsi, D Rodriguez, EP Wileyto, PG Shields, RF Tyndale. The Role of CYP2A6 in the Emergence of Nicotine Dependence in Adolescents. Pediatrics, 2007; 119(1):264-74.
AM Lee, J Yue and RF Tyndale. In vivo and in vitro characterization of chlorzoxazone metabolism and hepatic CYP2E1 levels in African Green monkeys; induction by chronic nicotine treatment. Drug Metab. and Disp. 2006; 34(9):1508-15.
M Joshi and RF Tyndale. Regional and cellular distribution of CYP2E1 in monkey brain and its induction by chronic nicotine. Neuropharmacol. 2006; 50 (5):568-575.
Contact Address:
University of Toronto
Department of Pharmacology & Toxicology
Room 4326, Medical Sciences Building
1 King's College Circle
Toronto, Ontario
M5S 1A8
Phone: [416] 978-6374
FAX: [416] 978-6395
Email: r.tyndale@utoronto.ca