Rachel F. Tyndale, Ph.D.
Professor, Pharmacology & Toxicology; Psychiatry
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.
A Zhu, C Renner, D Hatsukami, N Benowitz, RF Tyndale. CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska Native tobacco users. Addiction, 108(10):1818-28, 2013.
CS Ferguson, S Miksys, RM Palmour, RF Tyndale. Ethanol self-administration and nicotine treatment induce brain levels of CYP2B6 and CYP2E1 in African Green monkeys. Neuropharmacology, 72:74-81, 2013.
K Zhou, JY Khokhar, B Zhao, RF Tyndale. First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in rats. Biochem Pharmacol. 85(12):1848-55, 2013.
MJ Chenoweth, J O’Loughlin, M-P Sylvestre, RF Tyndale. CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers. Pharmacogenet and Genom. 23(4):232-5, 2013.
AZX Zhu, MJ Binnington, CC Renner, AP Lanier, DK Hatsukami, I Stepanov, CH Watson, CS Sosnof, NL Benowitz, RF Tyndale Alaska Native smokers and smokeless tobacco users with slower CYP2A6 activity have lower tobacco consumption, lower tobacco specific nitrosamine exposure and lower tobacco specific nitrosamine bioactivation. Carcinogenesis, 34(1):93-101, 2013.
AZX Zhu, L Sanderson Cox, N Nollen, M Mayo, B Faseru, KS Okuyemi, JS Ahluwalia, NL Benowitz, RF Tyndale. CYP2B6 and bupropion’s smoking–cessation pharmacology: the role of hydroxybupropion. Clin Pharm Ther. 92(6):771-7, 2012.
CS Ferguson, S Miksys, RM Palmour, RF Tyndale. Differential Effects of Nicotine Treatment and Ethanol Self-administration on CYP2A6, CYP2B6 and Nicotine Pharmacokinetics in African Green Monkeys. J Pharmacol Exper Ther. 343(3):628-37, 2012.
A Mann, SL Miksys, A Gaedigk, SJ Kish, DC Mash, and RF Tyndale. The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients. Neurobiol of Aging, 33: 2160–2171, 2012.
D Tang, B. Hello, M. Mroziewicz, L. Fellows, RF Tyndale., A. Dagher. Genetic variation in CYP2A6 predicts neural reactivity to smoking cues as measured using fMRI. NeuroImage, 60(4):2136-43 2012.
JY Khokhar and RF Tyndale. Rat brain CYP2B-enzymatic activation of chlorpyrifos to the oxon mediates cholinergic neurotoxicity. Toxicol Sci. 126(2):325-35 2012. (doi: 10.1093/toxsci/kfs029. PMID: 22287024).
JY Khokhar and RF Tyndale Drug metabolism within the brain changes drug response: Selective manipulation of brain CYP2B alters propofol response. Neuropsychopharmacology, 36(3): 692-700, 2011.
CA Wassenaar, Q Dong, Q Wei, CI Amos, MR Spitz, RF Tyndale. Combined Impact of CYP2A6 and CHRNA5-CHRNA3-CHRNB4 Variation on Smoking Behaviors and Lung Cancer Risk. J Nat Cancer Inst., 103(17):1342-6, 2011.
N Al Koudsi, EB Hoffmann, A Assadzadeh, and RF Tyndale. Hepatic CYP2A6 levels and nicotine metabolism: Impact of genetic, physiologic, environmental, and epigenetic factors. Eur J Clin Pharmacol. 66(3):239-51, 2010.
JC Mwenifumbo, Q Zhou, NL Benowitz, EM Sellers, RF Tyndale. New CYP2A6 gene deletion and conversion variants in a population of Black African descent. Pharmacogenomics, 11(2):189-98, 2010.
C Lerman, C Jepson, EP Wileyto, F Patterson, R Schnoll, M Mroziewicz, N Benowitz, RF Tyndale. Genetic Variation in Nicotine Metabolism Predicts the Efficacy of Extended Duration Transdermal Nicotine Therapy. Clin Pharmacol Ther. 87(5):553-7, 2010.
MK Ho, JC Mwenifumbo, N Al Koudsi, KS Okuyemi, JS Ahluwalia, NL Benowitz, RF Tyndale: Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers. Clin Pharmacol Ther. 85(6):635-43, 2009.
University of Toronto
Department of Pharmacology & Toxicology
Room 4326, Medical Sciences Building
1 King's College Circle
Phone:  978-6374
FAX:  978-6395