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Nicotine self-administration in mice is associated with rates of nicotine inactivation by CYP2A5

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Abstract

Rationale

Cyp2a5, the mouse homologue of human CYP2A6, encodes for the enzyme responsible for the primary metabolism of nicotine. Variation in human CYP2A6 activity can alter the amount smoked such as number of cigarettes smoked per day and smoking intensity. Different mouse strains self-administer different amounts of oral nicotine and quantitative trait loci analyses in mice suggested that Cyp2a5 may be involved in differential nicotine consumption behaviors.

Objectives

The goal of this study was to examine whether in vivo nicotine consumption levels were associated with CYP2A5 protein levels and in vitro nicotine metabolism in mice.

Methods

F2 mice propagated from high (C57Bl/6) and low (St/bJ) nicotine consuming mice were analyzed for CYP2A5 hepatic protein levels and in vitro nicotine metabolizing activity.

Results

We found that F2 male high-nicotine (n=8; 25.1±1.2 μg nicotine/day) consumers had more CYP2A5 protein, compared to low (n=11; 3.8±1.4 μg nicotine/day) consumers (10.2±1.0 vs 6.5±1.3 CYP2A5 units). High consumers also metabolized nicotine faster than the low consumers (6 μM: 0.18±0.04 vs 0.14±0.07; 30 μM: 0.36± 0.06 vs 0.26±0.13; 60 μM: 0.49±0.05 vs 0.32±0.17 nmol/min/mg). In contrast, female high- (25.1±2.1 μg nicotine/day) and low-nicotine (4.7±1.4 μg nicotine/day) consumers did not show pronounced differences in nicotine metabolism or CYP2A4/5 protein levels; this is consistent with other studies of sex differences in response to nicotine.

Conclusions

These data suggested that among male F2 mice, increased nicotine self-administration is associated with increased rates of nicotine metabolism, most likely, as a result of greater CYP2A5 protein levels.

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Abbreviations

CYP:

cytochrome P450

HNC:

high nicotine consumers

LNC:

low nicotine consumers

NCO:

nicotine C-oxidation

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Acknowledgements

We would like to thank Amir Boutrous for his assistance in protein analysis, Sharon Miksys and Meenal Joshi for guidance and critical review of the manuscript, and Helma Nolte and Raj Sharma for their assistance with HPLC assessment.

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Authors and Affiliations

  1. Centre for Addiction & Mental Health and the Department of Pharmacology, University of Toronto, Toronto, Canada

    Eric C. K. Siu & Rachel F. Tyndale

  2. Centre for Clinical Research in Neuropsychiatry, University of Western Australia, Crawley, Western Australia

    Dieter B. Wildenauer

Authors
  1. Eric C. K. Siu
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  2. Dieter B. Wildenauer
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  3. Rachel F. Tyndale
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Corresponding author

Correspondence to Rachel F. Tyndale.

Additional information

This study was supported by CAMH, CIHR 14173 & 53248, CIHR–Special Training Program in Tobacco Use in Special Populations and Ontario Graduate Scholarship (ECKS) and a Canada Research Chair in Pharmacogenetics (RFT).

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Siu, E.C.K., Wildenauer, D.B. & Tyndale, R.F. Nicotine self-administration in mice is associated with rates of nicotine inactivation by CYP2A5. Psychopharmacology 184, 401–408 (2006). https://doi.org/10.1007/s00213-006-0306-6

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  • DOI: https://doi.org/10.1007/s00213-006-0306-6

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