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Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

We investigated the role of genetic, physiological, environmental, and epigenetic factors in regulating CYP2A6 expression and nicotine metabolism.

Methods

Human livers (n = 67) were genotyped for CYP2A6 alleles and assessed for nicotine metabolism and CYP2A6 expression (mRNA and protein). In addition, a subset of livers (n = 18), human cryopreserved hepatocytes (n = 2), and HepG2 cells were used for DNA methylation analyses.

Results

Liver samples with variant CYP2A6 alleles had significantly lower CYP2A6 protein expression, nicotine C-oxidation activity, and affinity for nicotine. Female livers had significantly higher CYP2A6 protein and mRNA expression compared to male livers. Livers exposed to dexamethasone and phenobarbital had higher CYP2A6 expression and activity, however the difference was not statistically significant. Age and DNA methylation status of the CpG island and a regulatory site were not associated with altered CYP2A6.

Conclusions

We identified genotype, gender, and exposure to inducers as sources of variation in CYP2A6 expression and activity, but much variation remains to be accounted for.

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Acknowledgments

We thank Bin Zhao, Qian Zhou, Fariba Baghai Wadji, Sharon Miksys, Linda Liu, and Amandeep Mann for their technical assistance and Dr. Arturas Petronis for his valuable input in planning and analyzing the epigenetic experiments. This work was supported by the Centre for Addiction and Mental Health and Canadian Institutes for Health Research (CIHR) MOP86471. N.K. receives funding from CIHR-Strategic Training Program in Tobacco Use in Special Populations (TUSP) and Ontario Graduate Scholarship program (OGS). R.F.T. holds a Canada Research Chair in Pharmacogenetics.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Toronto, 1 King’s College Circle, Medical Sciences Building, Rm 4326, Toronto, ON, M5S 1A8, Canada

    Nael Al Koudsi, Ewa B. Hoffmann & Abbas Assadzadeh

  2. Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5S 2S1, Canada

    Ewa B. Hoffmann & Rachel F. Tyndale

  3. Department of Pharmacology and Toxicology and Psychiatry, University of Toronto, 1 King’s College Circle, Medical Sciences Building, Rm 4326, Toronto, ON, M5S 1A8, Canada

    Rachel F. Tyndale

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  1. Nael Al Koudsi
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  2. Ewa B. Hoffmann
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  3. Abbas Assadzadeh
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  4. Rachel F. Tyndale
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Correspondence to Rachel F. Tyndale.

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Al Koudsi, N., Hoffmann, E.B., Assadzadeh, A. et al. Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors. Eur J Clin Pharmacol 66, 239–251 (2010). https://doi.org/10.1007/s00228-009-0762-0

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  • DOI: https://doi.org/10.1007/s00228-009-0762-0

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