CYP2A enzymes metabolically inactivate nicotine and activate tobacco-derived procarcinogens [e.g., 4-[methylnitrosamino]-1-(3-pyridyl)-1-butanone]. Smoking decreases nicotine clearance, and chronic nicotine reduces hepatic CYP2A activity. However, little is known about the impact of smoking or nicotine on the expression of CYP2A in the lung. We investigated 1) the levels of human lung CYP2A mRNA in smokers versus nonsmokers and 2) the impact of daily nicotine treatment on lung CYP2A protein levels in African green monkeys (AGMs). Lung CYP2A13, CYP2A6, and CYP2A7 (and CYP1A2) mRNA levels in smokers and nonsmokers were assessed in Gene Expression Omnibus data sets (GSE30063, GSE108134, and GSE11784). The impact of chronic, twice-daily, subcutaneous nicotine at two doses (0.3 and 0.5 mg/kg) versus vehicle on lung CYP2A protein levels was assessed. The impact of ethanol self-administration was also investigated, with and without nicotine treatment. Smokers versus nonsmokers (from GSE30063 and GSE108134) had lower (1.04- to 1.12-fold) levels of lung CYP2A13, CYP2A6, and CYP2A7 (and higher CYP1A2) mRNA. Both doses of nicotine tested decreased AGM lung CYP2A protein (3- to 7-fold). Ethanol self-administration had no effect on AGM lung CYP2A protein, and there was no interaction between ethanol and nicotine. Our results suggest that smoking was associated with a reduction in human lung CYP2A13, CYP2A6, and CYP2A7 mRNA, consistent with the role of nicotine treatment in reducing AGM lung CYP2A protein. This regulation by smoking/nicotine will increase interindividual variation in lung CYP2A levels, which may impact the localized metabolism of inhaled drugs and tobacco smoke procarcinogens.

中文翻译：

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烟草烟雾/尼古丁对人和非洲绿猴肺中 CYP2A 表达的影响


CYP2A酶通过代谢使尼古丁失活并激活烟草衍生的致癌物[例如4-[甲基亚硝基氨基]-1-(3-吡啶基)-1-丁酮]。吸烟会降低尼古丁清除率，慢性尼古丁会降低肝脏 CYP2A 活性。然而，人们对吸烟或尼古丁对肺部 CYP2A 表达的影响知之甚少。我们研究了 1) 吸烟者与不吸烟者的人肺 CYP2A mRNA 水平，以及 2) 每日尼古丁治疗对非洲绿猴 (AGM) 肺 CYP2A 蛋白水平的影响。在基因表达综合数据集（GSE30063、GSE108134 和 GSE11784）中评估吸烟者和非吸烟者的肺 CYP2A13、CYP2A6 和 CYP2A7（和 CYP1A2）mRNA 水平。评估了每天两次长期皮下注射两种剂量（0.3 和 0.5 mg/kg）尼古丁与载体相比对肺 CYP2A 蛋白水平的影响。还研究了在有或没有尼古丁治疗的情况下自我给药乙醇的影响。吸烟者与不吸烟者（来自 GSE30063 和 GSE108134）的肺 CYP2A13、CYP2A6 和 CYP2A7（以及更高的 CYP1A2）mRNA 水平较低（1.04 至 1.12 倍）。测试的两种尼古丁剂量均降低了 AGM 肺 CYP2A 蛋白（3 至 7 倍）。自我给药乙醇对AGM肺CYP2A蛋白没有影响，并且乙醇和尼古丁之间不存在相互作用。我们的结果表明，吸烟与人肺 CYP2A13、CYP2A6 和 CYP2A7 mRNA 的减少有关，这与尼古丁治疗减少 AGM 肺 CYP2A 蛋白的作用一致。吸烟/尼古丁的这种调节会增加肺部 CYP2A 水平的个体差异，这可能会影响吸入药物和烟草烟雾致癌物的局部代谢。