Lieber C S
Mount Sinai School of Medicine and Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, Bronx Veterans Affairs Medical Center, New York 10468, USA.
Alcohol Clin Exp Res. 1999 Jun;23(6):991-1007.
Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance and a number of associated disorders that develop in the alcoholic. These were elucidated by the discovery of the microsomal metabolism of ethanol. The physiologic role of this system comprises gluconeogenesis from ketones, fatty acid metabolism, and detoxification of xenobiotics, including ethanol. After chronic ethanol consumption, the activity of the microsomal ethanol-oxidizing system (MEOS) increases, with an associated rise in cytochromes P-450, especially CYP2E1. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans. The role of MEOS in vivo and its increase after chronic ethanol consumption was shown most conclusively in alcohol dehydrogenase-negative deer mice. Enhanced ethanol oxidation is associated with cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, there is increased conversion of known hepatotoxic agents (such as CCl4) to toxic metabolites, which may explain the enhanced susceptibility of alcoholics to the adverse effects of industrial solvents. CYP2E1 also has a high capacity to activate some commonly used drugs, such as acetaminophen, to their toxic metabolites, and to promote carcinogenesis (e.g., from dimethylnitrosamine). Moreover, catabolism of retinol is accelerated and there also is induction of microsomal enzymes involved in lipoprotein production, resulting in hyperlipemia. Contrasting with the chronic effects of ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs through competition for the at least partially shared microsomal pathway. In addition, metabolism by CYP2E1 results in a significant free radical release and acetaldehyde production which, in turn, diminish reduced glutathione (GSH) and other defense systems against oxidative stress. Acetaldehyde also forms adducts with proteins, thereby altering the functions of mitochondria and of repair enzymes. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP1A2 and CYP3A4, two other perivenular P-450s, can also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. By contrast, CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds were too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated lecithins extracted from soybeans, was discovered to decrease CYP2E1 activity. PPC (and its active component dilinoleoylphosphatidylcholine) also oppose hepatic oxidative stress and fibrosis. PPC is now being tested clinically for the prevention and treatment of liver disease in the alcoholic.
乙醇通过乙醇脱氢酶（ADH）氧化可解释乙醇的多种代谢效应，但无法解释酗酒者出现的耐受性及一些相关病症。乙醇微粒体代谢的发现阐明了这些问题。该系统的生理作用包括酮体的糖异生、脂肪酸代谢以及对外源性物质（包括乙醇）的解毒。长期摄入乙醇后，微粒体乙醇氧化系统（MEOS）的活性增加，细胞色素P - 450，尤其是CYP2E1也随之升高。在实验动物和人类中，这种诱导作用都与内质网的增殖有关。MEOS在体内的作用及其在长期摄入乙醇后的增加，在乙醇脱氢酶阴性的鹿鼠身上得到了最确凿的证明。乙醇氧化增强与其他药物代谢的交叉诱导有关，从而导致药物耐受性。此外，已知的肝毒性物质（如四氯化碳）向有毒代谢物的转化增加，这可能解释了酗酒者对工业溶剂不良反应的易感性增强。CYP2E1还具有很高的能力将一些常用药物（如对乙酰氨基酚）激活为其有毒代谢物，并促进致癌作用（如由二甲基亚硝胺引发）。此外，视黄醇的分解代谢加速，参与脂蛋白生成的微粒体酶也被诱导，导致高脂血症。与长期摄入乙醇的慢性影响相反，急性摄入乙醇会通过竞争至少部分共享的微粒体途径抑制其他药物的代谢。此外，CYP2E1的代谢会导致大量自由基释放和乙醛生成，进而减少还原型谷胱甘肽（GSH）及其他抗氧化应激的防御系统。乙醛还会与蛋白质形成加合物，从而改变线粒体和修复酶的功能。CYP2E1及其mRNA的增加在肝小叶中央静脉周围区域最为明显，该区域是肝脏损伤最严重的部位。另外两种中央静脉周围的P - 450，即CYP1A2和CYP3A4，也能维持乙醇的代谢，从而促进MEOS活性并可能导致肝损伤。相比之下，CYP2E1抑制剂可对抗酒精性肝损伤，但迄今为止可用的化合物毒性太大，无法用于临床。然而，最近发现，从大豆中提取的无害多不饱和卵磷脂混合物多烯磷脂酰胆碱（PPC）可降低CYP2E1的活性。PPC（及其活性成分二亚油酰磷脂酰胆碱）还可对抗肝脏氧化应激和纤维化。目前正在对PPC进行临床测试，以用于预防和治疗酗酒者的肝病。
