Identification of cytochrome P450 enzymes critical for lung tumorigenesis by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridy1)-1-butanone (NNK): insights from a novel Cyp2abfgs-null mouse
Identification of cytochrome P450 enzymes critical for lung tumorigenesis by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridy1)-1-butanone (NNK): insights from a novel Cyp2abfgs-null mouse
复制标题
DOI：
10.1093/carcin/bgu182
复制
发表时间：
2014-11-01
期刊：
影响因子：
4.7
通讯作者：
Ding, Xinxin
中科院分区：
文献类型：
--
作者：
Li, Lei;Megaraj, Vandana;Ding, Xinxin
由小鼠 Cyp2abfgs 基因簇编码的细胞色素 P450 (P450) 酶优先在呼吸道中表达。先前的研究表明，肺部 P450 介导的生物激活对于烟草特异性肺癌原致癌物 4-(methylnitrosam ino)-1-(3-pyridyI)-1-buta none (NNK) 诱导的肺部肿瘤发生是必要的，并且 CYP2A5 介导了 NNK 生物激活中值得注意的部分，但不是全部。 肺。本研究的目的是确定 Cyp2abfgs 基因簇编码的其他 P450 是否也在 NNK 肺肿瘤发生中发挥重要作用。生成了一种新型 Cyp2ablgs 缺失小鼠，其中所有 Cyp2a、2b、2g、2f 和 2s 基因均被删除。 Cyp2abfgs 缺失的小鼠能够存活、具有生育能力，并且没有明显的生理异常或其他 P450 表达的代偿性增加。测定野生型 (WT) 和 Cyp2abfgs 缺失小鼠的 NNK 体外生物活性以及 NNK 诱导的 DNA 加合和体内肺肿瘤发生；将结果与 Cyp2a5 缺失小鼠的先前研究结果进行了比较。与 INT 或 Cyp2a5 缺失小鼠相比，Cyp2abfgs 缺失小鼠在肺和肝脏微粒体中表现出显着较低的 NNK 生物激活率。与 WT 或 C3p2a5 缺失小鼠相比，Cyp2abfgs 缺失小鼠的肺 06-甲基鸟嘌呤 DNA 加合物水平也显着降低。此外，与WT或Cyp2a5缺失小鼠相比，C3p2ablgs缺失小鼠在低（50mg/kg）和高（200mg/kg）NNK剂量下对NNK诱导的肺部肿瘤发生有很大抵抗力。这些结果首次表明，CYP2A、2B、2F、26 和 2S 酶对于 NNK 诱导的肺肿瘤发生是不可或缺的。
Cytochrome P450 (P450) enzymes encoded by the mouse Cyp2abfgs gene cluster are preferentially expressed in the respiratory tract. Previous studies have demonstrated that pulmonary P450-mediated bioactivation is necessary for lung tumorigenesis induced by the tobacco-specific lung procarcinogen 4-(methylnitrosam ino)-1-(3-pyridyI)-1-buta none (NNK), and that CYP2A5 mediates a noteworthy fraction, but not all, of NNK bioactivation in the lung. The aim of this study was to determine whether other P450s encoded by the Cyp2abfgs gene cluster also play significant roles in NNK lung tumorigenesis. A novel Cyp2ablgs-null mouse was generated, in which all Cyp2a, 2b, 2g, 2f and 2s genes are deleted. The Cyp2abfgs-null mouse was viable, fertile and without discernible physiological abnormalities or compensatory increases in the expression of other P450s. NNK bioactivation in vitro and NNK-induced DNA adduction and lung tumorigenesis in vivo were determined for wild-type (WT) and Cyp2abfgs-null mice; the results were compared with previous findings from Cyp2a5 -null mice. The Cyp2abfgs-null mice exhibited significantly lower rates of NNK bioactivation in lung and liver microsomes, compared with either INT or Cyp2a5-null mice. The levels of lung 06-methyl guanine DNA adduct were also substantially reduced in Cyp2abfgs-null mice, compared with either WT or C3p2a5-null mice. Moreover, the C3p2ablgs-null mice were largely- resistant to NNK-induced lung tumorigenesis at both low (50 mg/kg) and high (200 mg/kg) NNK doses, in contrast to the WT or Cyp2a5 -null mice. These results indicate for the first time that, collectively, the CYP2A, 2B, 2F, 26, and 2S enzymes are indispensable for NNK-induced lung tumorigenesis.