Caro Andres A, Cederbaum Arthur I
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Annu Rev Pharmacol Toxicol. 2004;44:27-42. doi: 10.1146/annurev.pharmtox.44.101802.121704.
This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.
本综述描述了CYP2E1的一些生化和毒理学特性，特别是其与酒精代谢和毒性的关系，以及过表达人CYP2E1的人肝癌HepG2细胞系的建立。在过表达CYP2E1的HepG2细胞中，乙醇、多不饱和脂肪酸和铁具有细胞毒性。谷胱甘肽（GSH）似乎对保护HepG2细胞免受CYP2E1依赖性细胞毒性至关重要，并且由于谷氨酸半胱氨酸连接酶的活性和表达增加两倍，GSH水平升高。我们认为，GSH合成的这种上调是一种适应性反应，以减轻CYP2E1依赖性氧化应激和毒性。氧化应激状态的诱导似乎在CYP2E1依赖性细胞毒性中起核心作用。在表达CYP2E1的HepG2细胞中，线粒体膜电位降低，这种降低与正在发展的毒性具有相似的特征。酒精性肝损伤可能是一个涉及多种机制的多因素过程。我们认为，CYP2E1依赖性氧化应激、线粒体损伤和GSH稳态之间的联系促成了乙醇对肝脏的毒性作用。
