- Full (HTML) - Full (PDF) - Related EHP Articles - PubMed:Related Articles - PubMed:Citation - Cited in PMC - Purchase This Issue

Thomas Thum,^1,2* Veit J. Erpenbeck,^3* Julia Moeller,^1,3 Jens M. Hohlfeld,³ Norbert Krug,³ and Jürgen Borlak¹

¹Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany; ²Bayerische Julius-Maximilians Universität, Medizinische Klinik I, Würzburg, Germany; ³Immunology/Allergology and Clinical Inhalation, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany;

Abstract

Background: Cytochrome P450 monooxygenases (CYP) play an important role in the defense against inhaled toxicants, and expression of CYP enzymes may differ among various lung cells and tissue compartments.

Methods: We studied the effects of tobacco smoke in volunteers and investigated gene expression of 19 CYPs and 3 flavin-containing monooxygenases, as well as isoforms of gluthathione S-transferases (GST) and uridine diphosphate glucuronosyltransferases (UGT) and the microsomal epoxide hydrolase (EPHX1) in bronchoalveolar lavage cells and bronchial biopsies derived from smokers (n = 8) and nonsmokers (n = 10) . We also investigated gene expression of nuclear transcription factors known to be involved in the regulation of xenobiotic metabolism enzymes.

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. In bronchial biopsies of smokers, CYP1A1, CYP1B1, CYP2C9, GSTP1, and GSTA2 were induced, but 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 up-regulated in bronchoalveolar lavage cells of smokers.

Conclusions: We found gene expression of pulmonary xenobiotic metabolizing 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.

Key words: cytochrome P450 monooxygenases, metabolism, smoking, transcription factors, xenobiotic metabolizing enzymes. Environ Health Perspect 114: 1655–1661 (2006) . doi:10.1289/ehp.8861 available via http://dx.doi.org/ [Online 19 July 2006]

Address correspondence to J. Borlak, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany. Telephone: 49-511-5350-559. Fax: 49-511-5350-573. E-mail: borlak@item.fraunhofer.de

*These authors contributed equally to this work.

We thank C.R. Lai (Drug Research and Medical Biotechnology, Fraunhofer ITEM) and B. Volkmann (Immunology/Allergology and Clinical Inhalation, Fraunhofer ITEM) for technical assistance.

This work was supported by a grant from the Lower Saxony Ministry of Culture and Science to J.B.

The authors declare they have no competing financial interests.

Received 17 November 2005 ; accepted 19 July 2006.