Lieber C S
Alcohol Research and Treatment Center, Bronx VA Medical Center, New York 10468, USA.
Clin Chim Acta. 1997 Jan 3;257(1):59-84. doi: 10.1016/s0009-8981(96)06434-0.
Alcohol-induced tissue damage results from associated nutritional deficiencies as well as some direct toxic effects, which have now been linked to the metabolism of ethanol. The main pathway involves liver alcohol dehydrogenase which catalyzes the oxidation of ethanol to acetaldehyde, with a shift to a more reduced state, and results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver. More severe toxic manifestations are produced by an accessory pathway, the microsomal ethanol oxidizing system involving an ethanol-inducible cytochrome P450 (2E1). After chronic ethanol consumption, there is a 4- to 10-fold induction of 2E1, associated not only with increased acetaldehyde generation but also with production of oxygen radicals that promote lipid peroxidation. Most importantly, 2E1 activates many xenobiotics to toxic metabolites. These include solvents commonly used in industry, anaesthetic agents, medications such as isoniazid, over the counter analgesics (acetaminophen), illicit drugs (cocaine), chemical carcinogens, and even vitamin A and its precursor beta-carotene. Furthermore, enhanced microsomal degradation of retinoids (together with increased hepatic mobilization) promotes their depletion and associated pathology. Induction of 2E1 also yields increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. New therapies include adenosyl-L-methionine which, in baboons, replenishes glutathione, and attenuates mitochondrial lesions. In addition, polyenylphosphatidylcholine (PPC) fully prevents ethanol-induced septal fibrosis and cirrhosis, opposes ethanol-induced hepatic phospholipid depletion, decreased phosphatidylethanolamine methyltransferase activity and activation of hepatic lipocytes, whereas its dilinoleoyl species increases collagenase activity. Current clinical trials with PPC are targeted on susceptible populations, namely heavy drinkers at precirrhotic stages.
酒精诱导的组织损伤源于相关的营养缺乏以及一些直接的毒性作用，目前这些毒性作用已与乙醇的代谢相关联。主要途径涉及肝脏乙醇脱氢酶，它催化乙醇氧化为乙醛，使状态转变为更还原的状态，并导致代谢紊乱，如高乳酸血症、酸中毒、高血糖、高尿酸血症和脂肪肝。一条辅助途径，即微粒体乙醇氧化系统，涉及一种乙醇诱导的细胞色素P450（2E1），会产生更严重的毒性表现。长期摄入乙醇后，2E1会被诱导4至10倍，这不仅与乙醛生成增加有关，还与促进脂质过氧化的氧自由基产生有关。最重要的是，2E1会将许多外源性物质激活为有毒代谢物。这些物质包括工业中常用的溶剂、麻醉剂、药物如异烟肼、非处方镇痛药（对乙酰氨基酚）、非法药物（可卡因）、化学致癌物，甚至维生素A及其前体β-胡萝卜素。此外，类视黄醇微粒体降解增强（连同肝脏动员增加）会导致它们的消耗及相关病理变化。2E1的诱导还会使乙醛生成增加，形成蛋白质加合物，导致抗体产生、酶失活、DNA修复减少、氧利用受损、谷胱甘肽耗竭、自由基介导的毒性、脂质过氧化以及胶原蛋白合成增加。新的治疗方法包括腺苷-L-甲硫氨酸，在狒狒身上，它能补充谷胱甘肽并减轻线粒体损伤。此外，多烯磷脂酰胆碱（PPC）能完全预防乙醇诱导的间隔纤维化和肝硬化，对抗乙醇诱导的肝脏磷脂消耗、磷脂酰乙醇胺甲基转移酶活性降低以及肝星状细胞激活，而其二月桂酰形式会增加胶原酶活性。目前使用PPC的临床试验针对的是易感人群，即肝硬化前期的重度饮酒者。
