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Expression of xenobiotic metabolizing enzymes in different lung compartments of smokers and nonsmokers
Background. Cytochrome P450 monooxygenases (CYP) play an important role in the defense against inhaled toxicants and expression of CYP enzymes may differ amongst various lung cells and tissue compartments.
Design and Participants. We studied the effects of tobacco smoke in volunteers and investigated gene expression of 19 cytochrome P450 monooxygenases, 3 flavine-containing monooxygenases, as well as isoforms of the gluthathione Sand UDP glucuronide transferases (GST, UGT) and the microsomal epoxide hydrolase (EPHX1) in bronchoalveolar lavage cells and bronchial biopsies derived from smokers (n=8) and non-smokers (n=10). Gene expression of nuclear transcription factors known to be involved in the regulation of xenobiotic metabolism enzymes was additionally investigated.
Results. Gene expression of CYP1A1, CYP1B1, CYP2S1, GSTP1 and EPHX1 was induced in bronchoalveolar lavage cells of smokers, whereas expression of CYP2B6/7, CYP3A5 and UGT2A1 was repressed. Specifically,CYP1A1, CYP1B1, CYP2C9, GSTP1 GSTA2 were induced in bronchial biopsies of smokers, whereas CYP2J2, and EPHX1 were repressed. Induction of CYP1A1 and CYP1B1 transcript abundance resulted in increased activity of the coded enzyme. Finally, expression of the liver-X-receptor and the glucocorticoid receptor was significantly upregulated in bronchoalveolar lavage cells of smokers.
Conclusions. We found gene expression of pulmonary xenobiotic metabolising enzymes and certain key transcription factors to be regulated in bronchoalveolar lavage cells and bronchial biopsies of smokers. The observed changes demonstrate tissue specificity in xenobiotic metabolism with likely implications for the metabolic activation of procarcinogens to ultimate carcinogens of tobacco smoke