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.
 

PubMed

Selected Publications:

  1. JY Khokhar, RF Tyndale. Drug metabolism within the brain changes drug response: selective manipulation of brain CYP2B alters propofol effects. Neuropsychopharmacology, 36(3): 692-700, 2011. (PMID: 21107310, PMCID: PMC 3055692)
  2. CA Wassenaar, Q Dong, Q Wei, CI Amos, MR Spitz, RF Tyndale. Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. Journal National Cancer Institute, 103(17):1342-6, 2011. (PMID: 21747048, PMCID: PMC 3168937)
  3. A Mann, SL Miksys, A Gaedigk, SJ Kish, DC Mash, RF Tyndale.  The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients. Neurobiology of Aging, 33:2160–71, 2012.     (PMID: 21958961)
  4. 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. Journal Pharmacology Experimental Therapeutics 343(3):628-37, 2012. (PMID: 22935730)
  5. AZ Zhu, LS Cox, N Nollen, B Faseru, KS Okuyemi, JS Ahluwalia, NL Benowitz, RF Tyndale. CYP2B6 and bupropion’s smoking–cessation pharmacology: the role of hydroxybupropion. Clinical Pharmacology and Therapeutics 92(6):771-7, 2012.  (PMID: 23149928, PMCID: PMC3729209)
  6. AZ 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)
  7. MJ Chenoweth, J O’Loughlin, MP 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)
  8. AZ Zhu, Q Zhou; LS 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, PMCID: PMC4111775)
  9. 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).
  10. DM McMillan, RF Tyndale. Nicotine increases codeine analgesia through the induction of brain CYP2D and central activation of codeine to morphine. Neuropsychopharmacology  40(7):1804-12, 2015 (PMID: 25630571)
  11. 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)
  12. 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 Selected as a Priority Communication. This means that, during the review of your article, it was considered to have particularly high scientific priority and will be identified as such when it is published. 81(7):554-563 2017 (PMID: 27865452)

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

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