Hong Feng, Liu Xiyu, Ward Stephen S, Xiong Huabao, Cederbaum Arthur I, Lu Yongke
Institute of Liver Diseases, Affiliated Hospital of Jining Medical University, Jining, China.
Department of Hepatobiliary and Pancreatic Surgery, The First Bethune Hospital, Jilin University, Jilin, China.
Dig Liver Dis. 2015 Jun;47(6):470-7. doi: 10.1016/j.dld.2015.02.012. Epub 2015 Mar 6.
Ethanol can induce cytochrome P450 2E1, an active generator of reactive oxygen species, and this cytochrome is considered a risk factor for oxidative liver injury. Recently, we found that in addition to P450 2E1 also cytochrome P450 2A5, another isoform of cytochrome P450, can be induced by ethanol, and that ethanol induction of cytochrome P450 2A5 is P450 2E1-dependent.
To investigate the role of cytochrome P450 2A5 in alcohol-induced liver injury.
Cytochrome P450 2A5-knockout mice and wild type mice were fed the Lieber-Decarli ethanol liquid diet to induce liver injury. Controls were fed the Lieber-Decarli control diet.
After 4 weeks of feeding with Lieber-Decarli diet, ethanol-induced liver injury was enhanced in the knockout mice compared with wild type mice, as indicated by serum transaminases, hepatic fat accumulation (steatosis), and necroinflammation observed in liver sections with Haematoxylin & Eosin staining. Ethanol-induced oxidative stress was also higher in the knockout mice than the wild types. Ethanol feeding induced cytochrome P450 2A5 in wild type mice but not in the knockout mice, while induction of cytochrome P450 2E1 was comparable in the knockout and wild type mice.
These results suggest that cytochrome P450 2A5 protects against ethanol-induced oxidative liver injury.
乙醇可诱导细胞色素P450 2E1，这是一种活性氧物质的生成酶，该细胞色素被认为是氧化肝损伤的一个危险因素。最近，我们发现除了P450 2E1外，细胞色素P450的另一种同工酶细胞色素P450 2A5也可被乙醇诱导，且乙醇对细胞色素P450 2A5的诱导依赖于P450 2E1。
研究细胞色素P450 2A5在酒精性肝损伤中的作用。
给细胞色素P450 2A5基因敲除小鼠和野生型小鼠喂食Lieber-Decarli乙醇液体饲料以诱导肝损伤。对照组喂食Lieber-Decarli对照饲料。
用Lieber-Decarli饲料喂养4周后，与野生型小鼠相比，基因敲除小鼠的乙醇诱导性肝损伤增强，这可通过血清转氨酶、肝脏脂肪堆积（脂肪变性）以及苏木精和伊红染色的肝脏切片中观察到的坏死性炎症来表明。基因敲除小鼠中乙醇诱导的氧化应激也高于野生型小鼠。乙醇喂养可诱导野生型小鼠中的细胞色素P450 2A5，但不能诱导基因敲除小鼠中的该细胞色素，而细胞色素P450 2E1的诱导在基因敲除小鼠和野生型小鼠中相当。
这些结果表明细胞色素P450 2A5可预防乙醇诱导的氧化肝损伤。
