Kessova Irina, Cederbaum Arthur I
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Curr Mol Med. 2003 Sep;3(6):509-18. doi: 10.2174/1566524033479609.
Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. CYP2E1 is of interest because of its ability to metabolize and activate many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of HepG2 cell lines developed to constitutively express the human CYP2E1 in assessing the actions of CYP2E1. Regulation of CYP2E1 is quite complex and will be briefly reviewed. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.
乙醇诱导的氧化应激似乎在乙醇导致肝损伤的机制中起主要作用。许多途径被认为与乙醇诱导氧化应激状态的能力有关。一条核心途径似乎是乙醇对细胞色素P450酶的CYP2E1形式的诱导。CYP2E1之所以受到关注，是因为它能够将包括乙醇在内的许多毒理学底物代谢并激活为更具反应性的有毒产物。在各种生理和病理生理条件下以及急性和慢性酒精处理后，CYP2E1的水平都会升高。CYP2E1也是活性氧如超氧阴离子自由基和过氧化氢的有效产生者，并且在铁催化剂存在的情况下，会产生强大的氧化剂如羟基自由基。这篇综述文章总结了CYP2E1的一些生化和毒理学特性，并简要描述了为组成性表达人CYP2E1而开发的HepG2细胞系在评估CYP2E1作用方面的应用。CYP2E1的调节相当复杂，将进行简要综述。将讨论通过抑制CYP2E1或CYP2E1依赖性氧化应激来治疗酒精性肝损伤的可能治疗意义，随后是一些可能有助于理解CYP2E1的作用及其在酒精性肝损伤中的作用的未来方向。
