Alcoholic Liver Disease: from CYP2E1 to CYP2A5.
Alcoholic Liver Disease: from CYP2E1 to CYP2A5.
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DOI：
10.2174/1874467208666150817111846
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发表时间：
2017
影响因子：
2.7
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Leung TM;Lu Y
本文就CYP 2 E1介导的酒精性肝损伤、酒精对CYP 2A 5的诱导作用及其机制，特别是CYP 2 E1在酒精诱导CYP 2A 5中的作用、CYP 2 E1-ROS-Nrf 2通路以及CYP 2A 5对酒精性氧化性肝损伤的保护作用等方面的研究进展作一综述。乙醇可诱导活性氧（ROS）的活性产生者CYP 2 E1，CYP 2 E1是乙醇诱导的氧化性肝损伤的促成因素。CYP 2A 5是细胞色素P450的另一种亚型，也可以被乙醇诱导。与配对喂养的对照组相比，长期喂食乙醇可增加野生型小鼠的CYP 2A 5催化活性、蛋白质和mRNA水平。这种诱导在CYP 2 E1敲除（cyp 2 e1 −/−）小鼠中减弱，但当人CYP 2 E1重新引入并在cyp 2 e1 −/−小鼠中表达时恢复。乙醇诱导的CYP 2 E1与CYP 2A 5共定位，并先于CYP 2A 5升高。抗氧化剂N-乙酰半胱氨酸和维生素C降低了酒精对ROS的升高，减弱了酒精对CYP 2A 5的诱导作用，但对CYP 2 E1没有影响，这表明ROS在CYP 2 E1和CYP 2A 5之间的串扰中发挥了新的作用。抗氧化剂阻断了Nrf 2的激活，Nrf 2是一种已知上调CYP 2A 5表达的转录因子。当Nrf 2敲除（Nrf 2 −/−）小鼠中酒精诱导的肝损伤增强时，Nrf 2 −/−小鼠中CYP 2A 5（而非CYP 2 E1）的酒精升高也较低。与WT小鼠相比，CYP 2A 5敲除（cyp 2a 5 −/−）小鼠表现出增强的酒精性肝损伤，如血清ALT、脂肪变性和坏死性炎症所示。在cyp 2a 5 −/−小鼠中观察到酒精诱导的高血糖症，但在WT小鼠中未观察到。
This article reviews recent studies on CYP2E1-mediated alcoholic liver injury, the induction of CYP2A5 by alcohol and the mechanism for this upregulation, especially the permissive role of CYP2E1 in the induction of CYP2A5 by alcohol and the CYP2E1-ROS-Nrf2 pathway, and protective effects of CYP2A5 against ethanol-induced oxidative liver injury. Ethanol can induce CYP2E1, an active generator of reactive oxygen species (ROS), and CYP2E1 is a contributing factor for alcohol-induced oxidative liver injury. CYP2A5, another isoform of cytochrome P450, can also be induced by ethanol. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity, protein and mRNA levels as compared to pair-fed controls. This induction was blunted in CYP2E1 knockout (cyp2e1−/−) mice but was restored when human CYP2E1 was reintroduced and expressed in cyp2e1−/− mice. Ethanol-induced CYP2E1 co-localized with CYP2A5 and preceded the elevation of CYP2A5. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol elevation of ROS and blunted the alcohol induction of CYP2A5, but not CYP2E1, suggesting ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. The antioxidants blocked the activation of Nrf2, a transcription factor known to upregulate expression of CYP2A5. When alcohol-induced liver injury was enhanced in Nrf2 knockout (Nrf2−/−) mice, alcohol elevation of CYP2A5 but not CYP2E1 was also lower in Nrf2−/− mice. CYP2A5 knockout (cyp2a5−/−) mice exhibited an enhanced alcoholic liver injury compared with WT mice as indicated by serum ALT, steatosis and necroinflammation. Alcohol-induced hyperglycemia were observed in cyp2a5−/− mice but not in WT mice.
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