Faculty: Rachel F. Tyndale, PhD
Professor, Pharmacology & Toxicology; Psychiatry
Endowed Chair in Addictions
Centre for Addiction and Mental Health
General Research Areas: 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 animal behaviour, biochemical, pharmacokinetic and molecular biological techniques.
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. (PMID: 23027621, PMCID: PMC3534190)
T Liu, RF Tyndale, SP David, H Wang, X-Q Yu, W Chen, X-Z Wen, W-Q Chen. Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers. Journal of Human Hypertension 27(1):24-30, 2013 (PMID: 22217675)
I Esterlis, JO Hannestad, E Perkins, F Bois, DC D’Souza, RF Tyndale, JP Seibyl, DM Hatsukami, KP Cosgrove, SS O’Malley. Effect of a nicotine vaccine on nicotine binding to the beta2-nAChRs in vivo in human tobacco smokers. American J Psychiatry 170(4):399-407, 2013 (PMID: 23429725, PMCID: PMC3738000).
MJ Chenoweth, J O’Loughlin, M-P Sylvestre, RF Tyndale. CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers. Pharmacogenetics and Genomics 23(4):232-5, 2013. (PMID: 23462429, PMCID: PMC3744214).
K Zhou, JY Khokhar, B Zhao, RF Tyndale. First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in rats. Biochem Pharmacol15;85(12):1848-55, 2013. (PMID: 23623752, PMCID: PMC3687523) S Miksys, SLT Cappendijk, WM Perry, B Zhao, RF Tyndale. Nicotine Kinetics in Zebra Finches in vivo and in vitro. Drug Metabolism and Disposition 41(6):1240-6, 2013 (PMID:23530019).
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 (PMID: 23639433),
S Ogawa, J Surapisitchat, C Virtanen, M Ogawa, M Niapour, KS Sugamori, S Wang, L Tamblyn, C Guillemette, E Hoffmann, Z Bin, RR Laposa, RF Tyndale, DM Grant, G Keller. Three dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell-derived hepatocytes. Development 140(15):3285-96, 2013 (PMID: 23861064).
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 (PMID: 23692359, PMCID: PMC3775934).
D Dempsey, N Sambol, P Jacob III, E Hoffmann, RF Tyndale, and E Fuentes-Afflick, N Benowitz. CYP2A6 Genotype but not Age Determines Cotinine Half-life in Infants and Children. Clinical Pharmacology and Therapeutics 94(3):400-6, 2013 (PMID: 23714690, PMCID: PMC3820275).
J Cheng, Y Zhen, S Miksys, D Beyoğlu, KW Krausz, JR Idle, RF Tyndale, A-M Yu, JR Idle and FJ Gonzalez, Potential role of CYP2D6 in the central nervous system.Xenobiotica 43(11):973-84, 2013 (PMID: 23614566, PMCID: PMC3750078).
SD Alsharari, ECK Siu, RF Tyndale, MI Damaj. Pharmacokinetic and pharmacodynamics studies of nicotine after oral administration in mice: Effects of methoxsalen, a CYP2A5/6 inhibitor. Nicotine and Tobacco Research 16(1): 18-25, 2014 (PMID: 23884323, PMCID: PMC3864487).
M Piliguian, AZH Zhu, Q Zhou, NL Benowitz, JS Ahluwalia, L Sanderson Cox and RF Tyndale. Novel CYP2A6 variants identified in African Americans are associated with slow nicotine metabolism in vitro and in vivo. Pharmacogenetics and Genomics 24(2): 118-28, 2014 (PMID: 24305170, PMCID: PMC3931261).
MJ Chenoweth, AZX Zhu, L Sanderson Cox, JS Ahluwalia, NL Benowitz, and RF Tyndale. Variation in P450 oxidoreductase(POR) A503V and flavin containing monooxygenase (FMO)-3 E158K is associated with minor alterations in nicotine metabolism but does not alter cigarette consumption. Pharmacogenetics and Genomics24(3):172-6, 2014 (PMID: 24448396).
RA Schnoll, T George, L Hawk, P Cinciripini, P Wileyto, RF Tyndale. The Relationship between the Nicotine Metabolite Ratio and Three Self-Report Measures of Nicotine Dependence Across Sex and Race. Psychopharmacology 231(12):2515-23, 2014 (PMID: 2440213).
RT Miller, S Miksys, E Hoffmann, RF Tyndale. Ethanol self-administration and nicotine treatment induce brain levels of CYP2D in African green monkeys. British Journal of Pharmacology, 171(12):3077-88, 2014 (PMID: 2461166).
AZX Zhu; Q Zhou; L Sanderson Cox; SP David, JS Ahluwalia; NL Benowitz, RF Tyndale. Association of CHRNA5-A3-B4 SNP rs2036527 with smoking cessation therapy response in African American smokers. Clinical Pharmacology and Therapeutics, 96(2):256-65, 2014 (PMID:24733007).
J Khokhar and RF Tyndale. Intracerebroventricularly and Systemically delivered inhibitor of brain CYP2B (C8-Xanthate), even following Chlorpyrifos exposure, reduces chloripyrifos activation and toxicity in male rats. Toxicological Sciences, 140(1):49-60, 2014 (PMID:24798379).
EL Craig, B Zhao, JZ Cui, M Novalen, S Miksys, RF Tyndale. Nicotine Pharmacokinetics in Rats is altered as a function of Age, impacting the Interpretation of Animal Model Data, Drug Metabolism and Disposition, 42(9):1447-55, 2014 EPub (PMID: 24980255).
KLP Garcia, AD Lê and RF Tyndale. Effect of food training and training dose on nicotine self-administration in rats. Behavioural Brain Research, 4;274C:10-18, 2014 (PMID:25101539).
AZX Zhu; Q Zhou; L Sanderson Cox; JS Ahluwalia; NL Benowitz, RF Tyndale. Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion assisted smoking cessation outcomes. Drug Metabolism and Disposition in press (PMID: 25143296).
CA Wassenaar, DV Conti, S Das, P Chen, EH Cook, MJ Ratain, NL. Benowitz, Rachel F. Tyndale. UGT1A and UGT2B genetic variation alters nicotine and nitrosamine glucuronidation in European and African American smokers. Cancer Epidemiology Biomarkers and Prevention in press.
University of Toronto
Department of Pharmacology & Toxicology
Room 4326, Medical Sciences Building
1 King's College Circle
Phone:  978-6374
FAX:  978-6395