Lieber C S
Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center, New York, USA.
Alcohol Alcohol Suppl. 1994;2:315-26.
Alcohol affects the liver through metabolic disturbances associated with its oxidation. Redox changes produced by the hepatic alcohol dehydrogenase pathway affect lipid, carbohydrate and protein metabolism. Ethanol is also oxidized in liver microsomes by the ethanol-inducible cytochrome P4502E1, resulting in ethanol tolerance and selective hepatic perivenular damage. Furthermore, P4502E1 activates various xenobiotics, explaining the increased susceptibility of the heavy drinker to the toxicity of anesthetics, commonly used medications (i.e. isoniazid), analgesics (i.e. acetaminophen), and chemical carcinogens. Induction of microsomal enzymes also contributes to vitamin A depletion, enhances its hepatotoxicity and results in increased acetaldehyde generation from ethanol, with formation of protein adducts, glutathione depletion, free-radical-mediated toxicity, and lipid peroxidation. Chronic ethanol consumption strikingly enhances the number of hepatic collagen-producing activated lipocytes. Both in vivo (in our baboon model of alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and activated lipocytes) ethanol and/or its metabolite acetaldehyde increase collagen accumulation and mRNA for collagen. Gender differences are related, in part, to lower gastric ADH activity (with consequent reduction of first pass ethanol metabolism) in young women, decreased hepatic fatty acid binding protein and increased free-fatty acid levels as well as lesser omega-hydroxylation, all of which result in increased vulnerability to ethanol. Elucidation of the biochemical effects of ethanol are now resulting in improved therapy: in baboons, S-adenosyl-L-methionine attenuates the ethanol-induced glutathione depletion and associated mitochondrial lesions, and polyenylphosphatidylcholine opposes the ethanol-induced hepatic phospholipid depletion, the decrease in phosphatidylethanolamine methyltransferase activity and the activation of hepatic lipocytes, with full prevention of ethanol-induced septal fibrosis and cirrhosis; its dilinoleoyl species also increases collagenase activity in lipocytes. The efficacy of this compound in man is now being studied in randomized multicenter clinical trials.
酒精通过与其氧化相关的代谢紊乱影响肝脏。肝脏乙醇脱氢酶途径产生的氧化还原变化会影响脂质、碳水化合物和蛋白质代谢。乙醇还可在肝脏微粒体中被乙醇诱导的细胞色素P4502E1氧化，导致乙醇耐受性和选择性肝小叶中央静脉损伤。此外，P4502E1可激活各种外源性物质，这解释了酗酒者对麻醉剂、常用药物（如异烟肼）、镇痛药（如对乙酰氨基酚）和化学致癌物毒性的易感性增加。微粒体酶的诱导还会导致维生素A缺乏，增强其肝毒性，并导致乙醇生成乙醛增加，形成蛋白质加合物、谷胱甘肽耗竭、自由基介导的毒性和脂质过氧化。长期饮酒会显著增加肝脏中产生胶原蛋白的活化脂肪细胞数量。在体内（在我们的酒精性肝硬化狒狒模型中）和体外（在培养的肌成纤维细胞和活化脂肪细胞中），乙醇和/或其代谢产物乙醛都会增加胶原蛋白的积累和胶原蛋白的mRNA。性别差异部分与年轻女性较低的胃乙醇脱氢酶活性（从而减少首过乙醇代谢）、肝脏脂肪酸结合蛋白减少、游离脂肪酸水平增加以及ω-羟化作用减弱有关，所有这些都会导致对乙醇的易感性增加。对乙醇生化作用的阐明目前正在带来更好的治疗方法：在狒狒中，S-腺苷-L-蛋氨酸可减轻乙醇诱导的谷胱甘肽耗竭和相关的线粒体损伤，多烯磷脂酰胆碱可对抗乙醇诱导的肝脏磷脂耗竭、磷脂酰乙醇胺甲基转移酶活性降低和肝脂肪细胞活化，完全预防乙醇诱导的间隔纤维化和肝硬化；其二月桂酰形式还可增加脂肪细胞中的胶原酶活性。目前正在随机多中心临床试验中研究该化合物对人类的疗效。
