Expression of xenobiotic metabolizing enzymes in different lung compartments of smokers and nonsmokers.
Expression of xenobiotic metabolizing enzymes in different lung compartments of smokers and nonsmokers.
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DOI：
10.1289/ehp.8861
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发表时间：
2006-11
影响因子：
10.4
通讯作者：
Borlak, Jurgen
中科院分区：
文献类型：
--
作者：
Thum, Thomas;Erpenbeck, Veit J;Moeller, Julia;Hohlfeld, Jens M;Krug, Norbert;Borlak, Jurgen
细胞色素P450单加氧酶（Cytochrome P450 monooxygenases，CYP）在防御吸入性毒物中起重要作用，CYP酶的表达在不同的肺细胞和组织间可能存在差异。我们研究了吸烟对志愿者的影响，并调查了吸烟者（n = 8）和非吸烟者（n = 10）支气管肺泡灌洗细胞和支气管活检组织中19种CYP和3种含黄素单加氧酶的基因表达，以及谷胱甘肽S-转移酶（GST）和尿苷二磷酸葡萄糖醛酸转移酶（UGT）的亚型和微粒体环氧化物水解酶（EPHX 1）。我们还研究了已知参与调节异生物质代谢酶的核转录因子的基因表达。在吸烟者的支气管肺泡灌洗液细胞中，CYP 1A 1、CYP 1B 1、CYP 2S 1、GSTP 1和EPHX 1的基因表达被诱导，而CYP 2B 6/7、CYP 3A 5和UGT 2A 1的表达被抑制。在吸烟者的支气管活检中，CYP 1A 1、CYP 1B 1、CYP 2C 9、GST P1和GST A2被诱导，但CYP 2 J2和EPHX 1被抑制。诱导CYP 1A 1和CYP 1B 1转录丰度导致编码酶的活性增加。最后，吸烟者支气管肺泡灌洗液细胞中肝X受体和糖皮质激素受体的表达显著上调。我们发现吸烟者的支气管肺泡灌洗液细胞和支气管活检组织中，肺异生物质代谢酶和某些关键转录因子的基因表达受到调节。所观察到的变化表明异生物质代谢的组织特异性，与烟草烟雾的最终致癌物的前致癌物的代谢活化可能的影响。
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. 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. 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. 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.