Role of Mouse Cytochrome P450 Enzymes of the Cyp2abfgs Subfamilies in the Induction of Lung Inflammation by Cigarette Smoke Exposure
Role of Mouse Cytochrome P450 Enzymes of the Cyp2abfgs Subfamilies in the Induction of Lung Inflammation by Cigarette Smoke Exposure
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DOI：
10.1093/toxsci/kfz171
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发表时间：
2019-11-01
影响因子：
3.8
通讯作者：
Ding, Xinxin
中科院分区：
文献类型：
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作者：
Hartog, Matthew;Zhang, Qing-Yu;Ding, Xinxin
烟草烟雾（TS）的许多成分需要生物活化才能产生毒性作用，然而，很少有研究探讨生物活化酶在TS暴露的不良影响中的作用。这种知识差距是风险评估和化学预防工作不确定性的主要来源。我们的目的是测试的假设，细胞色素P450（P450）酶介导的生物活化是必不可少的TS烟雾诱导的肺毒性的发展，通过确定小鼠Cyp 2abfgs基因亚家族的P450酶的贡献，环境烟草烟雾（ETS）诱导的肺部炎症。将成年雌性野生型（WT）和Cyp 2abfgs-无效小鼠（均为C57 BL/6 J背景）间歇地暴露于过滤空气或ETS 1或2周。通过定量支气管肺泡灌洗液（BALF）中的炎性细胞、细胞因子、趋化因子和蛋白质以及组织病理学分析来评估肺部炎症。在暴露于ETS 4 h的小鼠中，测定了2种ETS组分萘（NA）和3-甲基吲哚（3 MI）的谷胱甘肽（GSH）结合物。在暴露于ETS的WT小鼠中观察到持续性巨噬细胞性和嗜酸性肺部炎症;其程度在暴露于ETS的Cyp 2abfgs缺失小鼠中显著降低。促炎细胞因子和趋化因子的水平，沿着总蛋白浓度，在来自暴露于ETS的WT小鼠的无细胞BALF中增加，但Cyp 2abfgs缺失小鼠没有。此外，在ETS暴露后，在WT小鼠的肺中检测到NA和3 MI的GSH缀合物，但在Cyp 2abfgs-null小鼠的肺中未检测到。这些结果首次提供了小鼠Cyp 2abfgs基因簇在ETS诱导的肺部炎症中起重要作用的体内证据。
Many constituents of tobacco smoke (TS) require bioactivation to exert toxic effects; however, few studies have examined the role of bioactivation enzymes in the adverse effects of TS exposure. This knowledge gap is a major source of uncertainty for risk assessment and chemoprevention efforts. Our aim is to test the hypothesis that cytochrome P450 (P450) enzyme-mediated bioactivation is essential to the development of TS exposure-induced lung toxicity, by determining the contributions of P450 enzymes in the mouse Cyp2abfgs gene subfamilies to environmental tobacco smoke (ETS)-induced lung inflammation. Adult female wildtype (WT) and Cyp2abfgs-null mice (both on C57BL/6J background) were exposed to filtered air or ETS, intermittently, for 1 or 2 weeks. Lung inflammation was assessed by quantification of inflammatory cells, cytokines, chemokines, and proteins in bronchoalveolar lavage fluid (BALF) and histopathological analysis. Glutathione (GSH) conjugates of 2 ETS constituents, naphthalene (NA), and 3-methylindole (3MI), were measured in mice exposed to ETS for 4 h. Persistent macrophagic and neutrophilic lung inflammation was observed in ETS-exposed WT mice; the extent of which was significantly reduced in ETS-exposed Cyp2abfgs-null mice. Levels of proinflammatory cytokines and chemokines, along with the total protein concentration, were increased in cell-free BALF from ETS-exposed WT mice, but not Cyp2abfgs-null mice. Additionally, GSH conjugates of NA and 3MI were detected in the lungs of WT, but not Cyp2abfgs-null, mice following ETS exposure. These results provide the first in vivo evidence that the mouse Cyp2abfgs gene cluster plays an important role in ETS-induced lung inflammation.