Equipe d'accueil EA4483, Faculté de Médecine Pôle Recherche, Université Lille Nord de France, 1 Place de Verdun, 59045 Lille, France.
Biochimie. 2011 Jun;93(6):1012-27. doi: 10.1016/j.biochi.2011.02.012. Epub 2011 Mar 3.
The lung is directly exposed to a wide variety of inhaled toxicants and carcinogens. In order to improve our knowledge of the cellular processing of these compounds in the respiratory tract, we investigated the mRNA expression level of 380 genes encoding xenobiotic-metabolizing enzymes (XME), transporters, nuclear receptors and transcription factors, in pulmonary parenchyma (PP), bronchial mucosa (BM) and tumoral lung tissues from 12 patients with non-small cell lung cancer (NSCLC). Using a high throughput quantitative real-time RT-PCR method, we found that ADH1B, CYP4B1, CES1 and GSTP1 are the major XME genes expressed both in BM and PP. Our results also documented the predominant role played by the xenosensor AhR in human lung. The gene expression profiles were different for BM and PP, with a tendency toward increased mRNA levels of phase I and phase II XME genes in BM, suggesting major differences in the initial stages of xenobiotic metabolism. Some of the significantly overexpressed genes in BM (i.e. CYP2F1, CYP2A13, CYP2W1, NQO1…) encode proteins involved in the bioactivation of procarcinogens, pointing out distinct susceptibility to xenobiotics and their toxic effects between these two tissue types. Additionally, interindividual differences in transcript levels observed for some genes may be of genetic origin and may contribute to the variability in response to environmental exposure and, consequently, in the risk of developing lung diseases. A global decrease in gene expression was observed in tumoral specimens. Some of the proteins are involved in the metabolism or transport of anti-cancer drugs and their influence in the response of tumors to chemotherapy should be considered. In conclusion, the present study provides an overview of the cellular response to toxicants and drugs in healthy and cancerous human lung tissues, and thus improves our understanding of the mechanisms of chemical carcinogenesis as well as cellular resistance to chemotherapy.
肺直接暴露于各种吸入性的毒物和致癌物中。为了提高我们对这些化合物在呼吸道中细胞处理的认识，我们调查了编码异生物质代谢酶（XME）、转运体、核受体和转录因子的 380 个基因在 12 例非小细胞肺癌（NSCLC）患者的肺实质（PP）、支气管黏膜（BM）和肿瘤肺组织中的 mRNA 表达水平。使用高通量定量实时 RT-PCR 方法，我们发现 ADH1B、CYP4B1、CES1 和 GSTP1 是在 BM 和 PP 中均表达的主要 XME 基因。我们的结果还记录了人肺中 xenosensor AhR 所起的主要作用。BM 和 PP 的基因表达谱不同，BM 中 I 相和 II 相 XME 基因的 mRNA 水平有升高的趋势，表明异生物质代谢的初始阶段存在较大差异。BM 中一些显著过表达的基因（即 CYP2F1、CYP2A13、CYP2W1、NQO1…）编码参与前致癌物生物活化的蛋白质，指出这两种组织类型对异生物质及其毒性作用具有不同的敏感性。此外，一些基因的转录水平的个体间差异可能具有遗传起源，并可能导致对环境暴露的反应性以及因此对肺部疾病的发展风险存在差异。在肿瘤标本中观察到基因表达的整体下降。一些蛋白质参与抗癌药物的代谢或转运，其对肿瘤对化疗的反应的影响应予以考虑。总之，本研究提供了健康和癌变人肺组织对毒物和药物的细胞反应的概述，从而提高了我们对化学致癌机制以及细胞对化疗的耐药性的理解。
