Rachel F. Tyndale, Ph.D.
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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.
Selected Publications:
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.
CS Ferguson, S Miksys, R Palmour, and RF Tyndale. Independent and combined effects of ethanol self-administration and nicotine treatment on hepatic CYP2E1 in African Green monkeys. Drug Metab and Dispos.39(12):2233-41, 2011.
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. Neurobiology of Aging, 2011 Sep 27. [Epub ahead of print].
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.
A Mann, RF Tyndale CYP2D6 enzyme neuroprotects against MPP+ toxicity in SH-SY5Y neuronal cells. Eur J Neurosci. 31(7):1185-93, 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.
S Miksys, RF Tyndale. In vivo brain cytochrome P450 activity demonstrated by mechanism-based enzyme inhibition. Neuropsychopharmacology, 34(3) : 634-40, 2009.
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.
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