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The influence of tobacco smoke/nicotine on CYP2A expression in human and African green monkey lungs
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  • Yuan Gao,
  • Sharon Miksys,
  • Roberta Palmour,
  • Rachel Tyndale
Yuan Gao
University of Toronto
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Sharon Miksys
University of Toronto
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Roberta Palmour
McGill University
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Rachel Tyndale
University of Toronto
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Abstract

BACKGROUND AND PURPOSE CYP2A enzymes metabolically inactivate nicotine and activate tobacco-derived procarcinogens (e.g. NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). Smoking decreases nicotine clearance, and chronic nicotine reduces hepatic CYP2A activity. However, little is known about the impact of smoking or nicotine on the expression of CYP2A in the lung. We investigated 1) the levels of human lung CYP2A mRNA in smokers versus non-smokers and 2) the impact of daily nicotine treatment on lung CYP2A protein levels in African Green Monkeys (AGM). EXPERIMENTAL APPROACH Lung CYP2A13, CYP2A6 and CYP2A7 (and CYP1A2) mRNA levels in smokers and non-smokers were assessed in Gene Expression Omnibus (GEO) datasets (GSE40364, GSE11874 and GSE103845). The impact of chronic twice daily subcutaneous nicotine at two doses (0.3 and 0.5 mg kg-1), versus vehicle, on lung CYP2A protein levels was assessed. The impact of ethanol self-administration was also investigated, with and without nicotine treatment. KEY RESULTS Smokers, versus non-smokers, had significantly lower levels of lung CYP2A13, CYP2A6 and CYP2A7 (and increased CYP1A2) mRNA in both GEO datasets. Nicotine treatment, at both doses, significantly decreased AGM lung CYP2A protein. Ethanol self-administration had no effect on AGM lung CYP2A protein, and there was no interaction between ethanol and nicotine. CONCLUSIONS AND IMPLICATIONS Smoking was associated with a reduction in human lung CYP2A13, CYP2A6, and CYP2A7 mRNA, consistent with the role of nicotine treatment in reducing AGM lung CYP2A protein. This regulation by smoking/nicotine will increase interindividual variation in lung CYP2A levels that may impact the localized metabolism of inhaled drugs and tobacco smoke procarcinogens.