Lieber C S
Alcohol Research and Treatment Center, VA Medical Center, Bronx, NY 10468.
J Toxicol Clin Toxicol. 1994;32(6):631-81. doi: 10.3109/15563659409017974.
Mechanisms of the toxicologic manifestations of ethanol abuse are reviewed. Hepatotoxicity of ethanol results from alcohol dehydrogenase-mediated excessive hepatic generation of nicotinamide adenine dinucleotide and acetaldehyde. It is now recognized that acetaldehyde is also produced by an accessory (but inducible) pathway, the microsomal ethanol-oxidizing system, which involves a specific cytochrome P450. It generates oxygen radicals and activates many xenobiotics to toxic metabolites, thereby explaining the increased vulnerability of heavy drinkers to industrial solvents, anesthetics, commonly used drugs, over-the-counter medications and carcinogens. The contribution of gastric alcohol dehydrogenase to the first pass metabolism of ethanol and alcohol-drug interactions is now recognized. Alcohol also alters the degradation of key nutrients, thereby promoting deficiencies as well as toxic interactions with vitamin A and beta-carotene. Conversely, nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other supernutrients include polyenylphosphatidylcholine, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in non-human primates. Thus, a better understanding of the pathology induced by ethanol has now generated improved prospects for therapy.
本文综述了乙醇滥用的毒理学表现机制。乙醇的肝毒性源于乙醇脱氢酶介导的肝脏中烟酰胺腺嘌呤二核苷酸和乙醛的过度生成。现在人们认识到，乙醛也可通过一条辅助（但可诱导）途径生成，即微粒体乙醇氧化系统，该系统涉及一种特定的细胞色素P450。它会产生氧自由基并将许多外源性物质激活为有毒代谢物，从而解释了酗酒者对工业溶剂、麻醉剂、常用药物、非处方药和致癌物的易感性增加。现在已经认识到胃乙醇脱氢酶对乙醇首过代谢和酒精与药物相互作用的作用。酒精还会改变关键营养素的降解，从而导致营养缺乏以及与维生素A和β-胡萝卜素的毒性相互作用。相反，营养缺乏可能会影响乙醇和乙醛的毒性，如谷胱甘肽的消耗所示，而S-腺苷-L-甲硫氨酸可改善这种消耗。其他超级营养素包括多烯磷脂酰胆碱，它已被证明可纠正酒精引起的肝脏磷脂酰胆碱消耗，并预防非人类灵长类动物的酒精性肝硬化。因此，对乙醇所致病理学的更好理解为治疗带来了更好的前景。
