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Research ArticleMetabolism, Transport, and Pharmacogenomics

Predictors of Variation in CYP2A6 mRNA, Protein, and Enzyme Activity in a Human Liver Bank: Influence of Genetic and Nongenetic Factors

Julie-Anne Tanner, Bhagwat Prasad, Katrina G. Claw, Patricia Stapleton, Amarjit Chaudhry, Erin G. Schuetz, Kenneth E. Thummel and Rachel F. Tyndale
Journal of Pharmacology and Experimental Therapeutics January 2017, 360 (1) 129-139; DOI: https://doi.org/10.1124/jpet.116.237594
Julie-Anne Tanner
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Bhagwat Prasad
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Katrina G. Claw
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Patricia Stapleton
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Amarjit Chaudhry
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Erin G. Schuetz
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Kenneth E. Thummel
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Rachel F. Tyndale
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada (J-A.T., R.F.T.); Department of Pharmacology and Toxicology (J-A.T., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Toronto, Ontario, Canada; Department of Pharmaceutics (B.P., K.G.C, K.E.T.) and Center for Exposures, Diseases, Genomics, and Environment (P.S.), University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (A.C., E.G.S.)
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Abstract

Cytochrome P450 2A6 (CYP2A6) metabolizes several clinically relevant substrates, including nicotine, the primary psychoactive component in cigarette smoke. Smokers vary widely in their rate of inactivation and clearance of nicotine, altering numerous smoking phenotypes. We aimed to characterize independent and shared impact of genetic and nongenetic sources of variation in CYP2A6 mRNA, protein, and enzyme activity in a human liver bank (n = 360). For the assessment of genetic factors, we quantified levels of CYP2A6, cytochrome P450 oxidoreductase (POR), and aldo-keto reductase 1D1 (AKR1D1) mRNA, and CYP2A6 and POR proteins. CYP2A6 enzyme activity was determined through measurement of cotinine formation from nicotine and 7-hydroxycoumarin formation from coumarin. Donor DNA was genotyped for CYP2A6, POR, and AKR1D1 genetic variants. Nongenetic factors assessed included gender, age, and liver disease. CYP2A6 phenotype measures were positively correlated to each other (r values ranging from 0.47–0.88, P < 0.001). Female donors exhibited higher CYP2A6 mRNA expression relative to males (P < 0.05). Donor age was weakly positively correlated with CYP2A6 protein (r = 0.12, P < 0.05) and activity (r = 0.20, P < 0.001). CYP2A6 reduced-function genotypes, but not POR or AKR1D1 genotypes, were associated with lower CYP2A6 protein (P < 0.001) and activity (P < 0.01). AKR1D1 mRNA was correlated with CYP2A6 mRNA (r = 0.57, P < 0.001), protein (r = 0.30, P < 0.001), and activity (r = 0.34, P < 0.001). POR protein was correlated with CYP2A6 activity (r = 0.45, P < 0.001). Through regression analyses, we accounted for 17% (P < 0.001), 37% (P < 0.001), and 77% (P < 0.001) of the variation in CYP2A6 mRNA, protein, and activity, respectively. Overall, several independent and shared sources of variation in CYP2A6 activity in vitro have been identified, which could translate to variable hepatic clearance of nicotine.

Footnotes

    • Received September 22, 2016.
    • Accepted November 2, 2016.
  • The authors acknowledge the support of the Endowed Chair in Addictions for the Department of Psychiatry (R.F.T.); National Institutes of Health Pharmacogenomics Research Network grants U01 DA020830 (R.F.T.), and P30 ES007033 (P.S., K.E.T.); Canadian Institutes of Health Research grant THM 109787 (R.F.T.); Campbell Family Mental Health Research Institute of the Centre for Addiction and Mental Health, the CAMH Foundation; the Canada Foundation for Innovation (nos. 20289 and 16014) (R.F.T.); and the Ontario Ministry of Research and Innovation. The work was also supported by the National Institutes of Health National Cancer Institute (Cancer Center Support Grant P30 CA21765) and the American Lebanese Syrian Associated Charities (ALSAC). Source of liver tissue: Liver Tissue Procurement and Distribution System (National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Contract N01-DK92310) and the Cooperative Human Tissue Network. Conflicts of interest: Dr. Tyndale has consulted for Apotex. The remaining authors declare no conflicts of interest.

  • A preliminary account of this work was previously presented at the following meeting: Tanner J-A, Chaudhry A, Bhagwat P, Schuetz EG, Thummel KE, and Tyndale RF (2016) Determination of predictors of CYP2A6 protein levels and nicotine metabolism in a human liver bank: influence of genetic and non-genetic factors, presented at the annual meeting of the Society for Research on Nicotine and Tobacco; 2016 March 2–5; Chicago, IL. Society For Research on Nicotine and Tobacco, Madison, WI.

  • dx.doi.org/10.1124/jpet.116.237594.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 360 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 360, Issue 1
1 Jan 2017
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Impact of Genetic and Nongenetic Factors on CYP2A6

Julie-Anne Tanner, Bhagwat Prasad, Katrina G. Claw, Patricia Stapleton, Amarjit Chaudhry, Erin G. Schuetz, Kenneth E. Thummel and Rachel F. Tyndale
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 129-139; DOI: https://doi.org/10.1124/jpet.116.237594

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Impact of Genetic and Nongenetic Factors on CYP2A6

Julie-Anne Tanner, Bhagwat Prasad, Katrina G. Claw, Patricia Stapleton, Amarjit Chaudhry, Erin G. Schuetz, Kenneth E. Thummel and Rachel F. Tyndale
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 129-139; DOI: https://doi.org/10.1124/jpet.116.237594
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