Faculty: Rachel F. Tyndale, PhD

Professor, Pharmacology & Toxicology; Psychiatry
Endowed Chair in Addictions
Head Pharmacogenetics
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.
 

Selected Publications:

[1] C Lerman, RA Schnoll, LW Hawk Jr, P Cinciripini, TP George, EP Wileyto, GE Swan, NL Benowitz, DF Heitjan, RF Tyndale; PGRN-PNAT Research Group. Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respiratory Medicine 3(2):131-8, 2015 (PMID: 25588294).

[2] CA Wassenaar, Y Ye, Q Cai, MC Aldrich, J Knight, M Spitz, X Wu, WJ Blot, RF Tyndale. CYP2A6 reduced activity gene variants confer reduction in lung cancer risk in African American Smokers--findings from two independent populations. Carcinogenesis 36(1):99-103, 2015 (PMID: 25416559, PMCID: PMC4291053)

[3] KL Garcia, K Coen, S Miksys, A D Lê, RF TYNDALE. Effect of brain CYP2B inhibition on brain nicotine levels and nicotine self-administration. Neuropsychopharmacology 40(8):1910-8, 2015 (PMID: 25652250)

[4] A Loukola, J Buchwald, R Gupta, T Palviainen, J Hällfors, E Tikkanen, T Korhonen, M Ollikainen, A-P Sarin, S Ripatti, T Lehtimäki, O Raitakari, V Salomaa, RJ Rose, RF Tyndale, J Kaprio. A genome-wide association study of a biomarker of nicotine metabolism. PLOS Genetics, 2015 Sep 25; 11(9):e1005498.doi: 10.1371/journal.pgen.1005498. (PMID: 26407342)

[5] JA Cunningham, V Kushnir, P Selby, RF Tyndale, L Zawertailo, ST Leatherdale. Effect of mailing nicotine patches on tobacco cessation among adult smokers: A randomized trial. JAMA Internal Medicine 176(2):184-90, 2016. (PMID: 26809849)

[6] I Boileau PhD, E Mansouri; B Williams; B Le Foll; PM Rusjan; R Mizrahi; RF Tyndale; MA Huestis; DE Payer; AA Wilson; S Houle; SJ Kish; J Tong. Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging with the novel radiotracer [11C]CURB. Biological Psychiatry, 80(9):691-701, 2016. (PMID: 27345297)

[7] S Li, Y Yang, E Hoffmann, RF Tyndale, EA Stein. CYP2A6 genetic variation alters striatal-cortical circuits, network hubs, and executive processing in smokers. Biological Psychiatry 81(7):554-563 2017 (PMID: 27865452)

[8] J-A Tanner, JA Henderson, D Buchwald, BV Howard, P Nez Henderson, RF Tyndale. Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer. Pharmacogenetics and Genomics, 27(5): 169-178, 2017 (PMID: 28181923)

[9] S Miksys, F Baghai Wadji, EC Tolledo, G Remington, JN Nobrega, RF Tyndale. Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms. Progress in Neuropsychopharmacology & Biological Psychiatry, 78:140-148, 2017. (PMID: 28454738)

[10] P Faulkner, D Ghahremani, RF TYNDALE, C Cox , AS Kazanjian, N Paterson, S Lotfipour, GS Hellemann, N Petersen, C Vigil, E London. Reduced-nicotine cigarettes in young smokers: impact of nicotine metabolism on nicotine dose effects, Neuropsychopharmacology, 42(8): 1610-18, 2017 (PMID: 28117337)

[11] AR Peng, M Morales, EP Wileyto, LW Hawk, Jr., P Cinciripini, TP George, NL Benowitz, NL Nollen, C Lerman, RF Tyndale, & R Schnoll. Measures and Predictors of Varenicline Adherence in the Treatment of Nicotine Dependence. Addictive Behaviors, 75C: 122-129, 2017 (PMID: 28728040)

[12] KLP Garcia, AD Lê, RF Tyndale, Brain CYP2B induction can decrease nicotine levels in the brain, Addiction Biology 22(5): 1257-66, 2017. (PMID: 27230546)

[13] DM McMillian and RF Tyndale. Inducing rat brain CYP2D with nicotine increases the rate of codeine tolerance; predicting the rate of tolerance from acute analgesic response. Biochemical Pharmacology, 145: 158-168, 2017. (PMID: 28837793)

[14] J-A Tanner, AZ Zhu, KG Claw, B Prasad, V Korchina, J Hu, HV Doddapaneni, DM Muzny, EG Schuetz, C Lerman, KE Thummel, SE Scherer, RF Tyndale. Novel CYP2A6 diplotypes identified through next-generation sequencing are associated with in vitro and in vivo nicotine metabolism. Pharmacogenetics and Genomics, 28(1): 7-16, 2018 (PMID: 29232328)

[15] T Taghavi, CA Arger, SH Heil, ST Higgins, RF Tyndale. Longitudinal Influence of Pregnancy on Nicotine Metabolic Pathways. Journal of Pharmacology and Therapuetics 364(2):238-245 2018 (PMID: 29158210)

[16] MJ Chenoweth, JJ Ware, AZX Zhu, CB Cole, LS Cox, N Nollen, JS Ahluwalia, NL Benowitz, RA Schnoll, LW Hawk Jr., PM Cinciripini, TP George, C Lerman, J Knight, RF Tyndale and on behalf of the PGRN-PNAT Research Group. Genome-wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences. Addiction doi: 10.1111/add.14032. [Epub ahead of print] (PMID: 28921760)

[17] DM McMillan, S Miksys, and RF Tyndale. Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia. Addiction Biology 2017, doi: 10.1111/adb.12590. [Epub ahead of print] (PMID: 29266563)

 

Contact:

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

Back to Top