HEPATIC, METABOLIC AND TOXIC EFFECTS OF ETHANOL - 1991 UPDATE
HEPATIC, METABOLIC AND TOXIC EFFECTS OF ETHANOL - 1991 UPDATE
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DOI：
10.1111/j.1530-0277.1991.tb00563.x
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发表时间：
1991-08-01
影响因子：
3.2
通讯作者：
LIEBER, CS
中科院分区：
文献类型：
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作者：
LIEBER, CS
直到二十年前，饮食不足被认为是酗酒者患肝病的唯一原因。随着人口整体营养状况的改善，人们更加重视继发性营养不良，并确定了乙醇的直接肝毒性作用。乙醇通过乙醇脱氢酶途径氧化产生的NADH产生氧化还原变化而具有肝毒性，这反过来影响脂质、碳水化合物、蛋白质和嘌呤的代谢。乙醇也在肝微粒体中被乙醇诱导的细胞色素P-450（P-450 IIE 1）氧化，这有助于乙醇代谢和耐受性，并将外源性物质活化为有毒自由基，从而解释了重度饮酒者对工业溶剂、麻醉剂、常用处方药、非处方止痛药、化学致癌物甚至营养因素（如维生素A）的脆弱性增加。此外，乙醇可降低肝脏维生素A水平，即使在给予含有大量维生素的饲料时也是如此，这部分反映了通过新发现的视黄醇代谢微粒体途径加速微粒体降解，可由乙醇或药物给药诱导。当乙醇和其他药物一起给药时，肝脏维生素A的消耗明显加剧，模拟了常见的临床事件。微粒体诱导也导致乙醛的产生增加。乙醛，反过来，通过形成蛋白质加合物引起损伤，导致抗体产生，酶失活，DNA修复减少，以及微管，质膜和线粒体的改变，氧利用率显著受损。乙醛还引起谷胱甘肽耗竭和脂质过氧化，并刺激维生素A储存细胞（脂肪细胞）和肌成纤维细胞产生肝胶原蛋白。实验上，肝损伤甚至纤维化可以被一些“超级营养素”，如S-腺苷-L-蛋氨酸或多不饱和卵磷脂减弱。因此，乙醇的营养和毒性作用之间的经典二分法现在已经被弥合。
Until two decades ago, dietary deficiencies were considered to be the only reason for alcoholics to develop liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition and direct hepatotoxic effects of ethanol were established. Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) that contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. In addition, ethanol depresses hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A is strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Microsomal induction also results in increased production of acetaldehyde. Acetaldehyde, In turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts. Experimentally, liver injury and even fibrosis can be attenuated by some "supernutrients," such as S-adenosyl-L-methionine or polyunsaturated lecithin. Thus, the classic dichotomy between nutritional and toxic effects of ethanol has now been bridged.