The role of Cytochrom P4502E1 in Alcoholic Liver Disease and alcohol mediated carcinogenesis
The role of Cytochrom P4502E1 in Alcoholic Liver Disease and alcohol mediated carcinogenesis
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DOI：
10.1055/a-0784-8815
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发表时间：
2019-01-01
影响因子：
1.3
通讯作者：
Mueller, Sebastian
中科院分区：
文献类型：
--
作者：
Seitz, Helmut Karl;Mueller, Sebastian
酒精性肝病（ALD）的发病机制和乙醇介导的致癌作用涉及多种因素。除了遗传、表观遗传和免疫学机制外，乙酰丙酮相关毒性、氧化应激以及奎宁介导的炎症也非常重要。氧化应激，随着活性氧（ROS）的产生，在炎症（酒精性肝炎）或乙醇通过细胞色素P4502E1（CYP2E1）氧化过程中发展。CYP2E1受乙醇诱导，将乙醇氧化为乙醛，并在此过程中产生ROS。ROS导致蛋白质损伤、增强的纤维化和DNA损伤。此外，CYP2E1诱导导致各种前致癌物的活化增强以及视黄醇和视黄酸（RA）（一种负责细胞分化和增殖的化合物）的降解增加。在动物实验中，CYP2E1的抑制导致ALD和化学诱导的致癌作用的改善。在人类中，CYP2E1在一周后每天消耗40克乙醇后被诱导。然而，诱导因个体而异。其机制尚不清楚。ALD患者表现出CYP2E1、高致癌性乙烯基DNA加合物的发生与纤维化严重程度之间的显著相关性。氯甲咪唑（一种特异性CYP 2E1抑制剂）对ALD的CYP 2E1抑制作用的初步结果预计很快就会公布。
Various factors are involved in the pathogenesis of alcoholic liver disease (ALD) and ethanol-mediated carcinogenesis. In addition to genetic, epigenetic and immunologic mechanisms, acetaldehyde-associated toxicity, oxidative stress as well as cytokine-mediated inflammation are of major importance. Oxidative stress, with the generation of reactive oxygen species (ROS), develops either in inflammation (alcoholic hepatitis) or during oxidation of ethanol via cytochrome P4502E1 (CYP2E1). CYP2E1 is induced by ethanol, oxidizes ethanol to acetaldehyde, and generates ROS during this process. ROS results in protein damage, enhanced fibrogenesis and DNA lesions. Furthermore, CYP2E1 induction results in an enhanced activation of various procarcinogens and an increased degradation of retinol and retinoic acid (RA), a compound responsible for cell differentiation and proliferation. An inhibition of CYP2E1 results in an improvement of ALD and chemically induced carcinogenesis in animal experiments. In humans, CYP2E1 is induced following the consumption of 40grams of ethanol per day after one week. However, the induction varies inter-individually. The mechanism for this is still unclear. Patients with ALD show a significant correlation between CYP2E1, the occurrence of highly carcinogenic etheno DNA adducts and the severity of fibrosis. First results on the effect of CYP2E1 inhibition by chlormethiazole, a specific CYP2E1 inhibitor on ALD, can be expected soon.