Lieber C S
Alcohol Research and Treatment Center, Bronx Department of Veterans Affairs Medical Center, New York, USA.
Physiol Rev. 1997 Apr;77(2):517-44. doi: 10.1152/physrev.1997.77.2.517.
The role of the microsomal ethanol-oxidizing system (MEOS) in hepatic ethanol metabolism is reviewed, with focus on its constitutive, ethanol-inducible cytochrome P-4502E1 (2E1). The MEOS was purified and reconstituted using 2E1, phospholipids, and cytochrome P-450 reductase and shown to oxidize ethanol to acetaldehyde, mainly as a monooxygenase and secondarily via hydroxyl radicals, with transcriptional and posttranscriptional regulation. Polymorphism of 2E1 was recognized, and enzymology (including cofactors, role of lipids, inducers, and inhibitors) as well as cellular and tissue distribution were chartered. Physiological functions involve lipid metabolism and ketone utilization in starvation, obesity, and diabetes. The most significant role of 2E1 is its adaptive response to high blood ethanol levels with a corresponding acceleration of ethanol metabolism. The associated free radical production, however, contributes to liver injury in the alcoholic. Most importantly, 2E1 has a unique capacity to activate many xenobiotics (85 of which are listed) to hepatotoxic or carcinogenic products. Induction of 2E1 also results in enhanced production of acetaldehyde, a highly reactive and toxic metabolite. The proliferation of the endoplasmic reticulum associated with 2E1 induction is also accompanied by enhanced activity of other cytochrome P-450s, resulting in accelerated metabolism of, and tolerance to, other drugs, as well as increased degradation of retinol and its hepatic depletion. Some substrates and metabolites, however, are innocuous and may eventually be used as markers of heavy drinking. Recently discovered effective 2E1 inhibitors also have great therapeutic potential.
本文综述了微粒体乙醇氧化系统（MEOS）在肝脏乙醇代谢中的作用，重点关注其组成型、乙醇诱导型细胞色素P-4502E1（2E1）。MEOS利用2E1、磷脂和细胞色素P-450还原酶进行纯化和重组，并显示主要作为单加氧酶、其次通过羟基自由基将乙醇氧化为乙醛，存在转录和转录后调控。2E1的多态性得到确认，并对其酶学（包括辅因子、脂质的作用、诱导剂和抑制剂）以及细胞和组织分布进行了研究。其生理功能涉及饥饿、肥胖和糖尿病状态下的脂质代谢和酮体利用。2E1最重要的作用是对高血乙醇水平的适应性反应，伴随乙醇代谢相应加速。然而，相关的自由基产生会导致酒精性肝病患者的肝脏损伤。最重要的是，2E1具有独特的能力，可将许多外源性物质（列出了其中85种）激活为肝毒性或致癌产物。2E1的诱导还会导致乙醛生成增加，乙醛是一种高反应性和有毒的代谢产物。与2E1诱导相关的内质网增殖还伴随着其他细胞色素P-450活性增强，导致其他药物的代谢加速和耐受性增加，以及视黄醇降解增加及其肝脏耗竭。然而，一些底物和代谢产物是无害的，最终可能用作大量饮酒的标志物。最近发现的有效的2E1抑制剂也具有巨大的治疗潜力。
