Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver
Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver
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DOI：
10.1002/hep.20532
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发表时间：
2005-02-01
期刊：
影响因子：
13.5
通讯作者：
Rusyn, I
中科院分区：
文献类型：
--
作者：
Bradford, BU;Kono, H;Rusyn, I
基于流行病学证据，上消化道和肝脏恶性肿瘤的发生与乙醇的消耗有很大的因果关系。人们普遍认为，氧化剂在酒精性肝损伤中起关键作用；然而，目前尚不清楚氧化剂如何参与DNA损伤。我们询问是否烟酰胺腺嘌呤二核苷酸磷酸氧化酶，细胞色素P450 CYP2E1，或两者都负责DNA损伤的产生。采用鼠类灌胃乙醇模型。使用Wistar大鼠、Cyp2e1-、p47(phax)-null和hCyp2e1转基因小鼠。测定了氧化DNA加合物、致突变性无尿嘧啶/无嘧啶位点的丰度以及碱基切除DNA修复基因的表达。在大鼠和野生型小鼠中，乙醇处理4周导致氧化性DNA损伤增加，并诱导碱基切除DNA修复基因的表达，该基因已知可去除氧化性DNA损伤。在酒精处理的cyp2e1缺失小鼠中，没有观察到这两个终点的增加，而p47（phax）缺失小鼠和转基因hCyp2e1的反应程度与野生型相同。P450抑制剂1-氨基苯并三唑完全消除了DNA修复基因表达的增加。综上所述，这些数据支持了乙醇诱导肝脏DNA氧化应激的假设。此外，尽管有研究表明烟酰胺腺嘌呤二核苷酸磷酸氧化酶衍生的氧化剂对乙醇诱导的肝损伤的发展至关重要，但CYP2E1是诱导DNA氧化应激所必需的，因此可能在乙醇相关的肝癌发生中发挥关键作用。
The occurrence of malignant tumors of the upper gastrointestinal tract and liver is, based largely on epidemiological evidence, causally related to the consumption of ethanol. It is widely recognized that oxidants play a key role in alcohol-induced liver injury; however, it is unclear how oxidants may be involved in DNA damage. We asked whether nicotinamide adenine dinucleotide phosphate oxidase, cytochrome P450 CYP2E1, or both are responsible for the production of DNA damage. The rodent Tsukamoto-French model of intragastric ethanol infitsion was used. Wistar rats, Cyp2e1-, p47(phax)-null, and hCyp2e1 transgenic mice were used. The abundance of oxidative DNA adducts, mutagenic apurinic/apyrimidinic sites, and expression of base excision DNA repair genes was determined. In rats and wild-type mice, ethanol treatment for 4 weeks led to an increase in oxidative DNA damage and induction of expression of the base excision DNA repair genes that are known to remove oxidative DNA lesions. No increase in either of the endpoints was observed in ethanol-treated Cyp2e1-null mice, whereas the magnitude of response in p47(phax)-null mice and transgenic hCyp2e1 was identical to that in wild types. The increase in expression of DNA repair genes was completely abolished by treatment with the P450 inhibitor 1-aminobenzotriazole. In conclusion, the data support the hypothesis that oxidative stress to DNA is induced in liver by ethanol. Furthermore, although it was shown that nicotinamide adenine dinucleotide phosphate oxidase-derived oxidants are critical for the development of ethanol-induced liver injury, CYP2E1 is required for the induction of oxidative stress to DNA, and thus may play a key role in ethanol-associated hepatocarcinogenesis.