The metabolism of ethanol and its metabolic effects.
The metabolism of ethanol and its metabolic effects.
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乙醇的代谢及其代谢效应。
作者：
R. Hawkins;H. Kalant
尽管在过去的十年中对乙醇的代谢进行了大量的研究，但关于这种代谢的途径和控制它的因素的情况并没有根本改变。过氧化氢酶肯定可以在体外氧化乙醇，并且潜在的H22产生系统存在于细胞内，但迄今为止还没有明确的证据支持乙醇在体内被过氧化氢酶系统代谢的观点。类似地，肝微粒体酶可以通过涉及NADPH和氧的反应（MEOS）在体外氧化乙醇，但大量证据表明，在单次或重复给予乙醇后，该反应在体内没有显著作用。慢性乙醇摄入后MEOS活性的增加反映了肝细胞中平滑内质网的增加，但这可能与乙醇对脂质代谢的影响有关，而不是与乙醇本身的代谢有关。
涉及乙醇与葡萄糖醛酸、脂肪酸或其他物质的酯化或缩合的其他途径在乙醇代谢中发挥着数量上微不足道的作用。这些反应的意义在于乙醇和其他物质之间的相互作用，这些物质可能竞争相同的代谢途径。
乙醇脱氢酶（ADH）无疑是乙醇氧化过程中最重要的酶。它可能解毒胃肠道中产生的少量乙醇，但其动力学特性表明，其在体内的主要作用涉及一些其他底物比乙醇。事实上，ADH似乎是一组酶，每一种酶在体内可能具有不同的主要作用。ADH活性测定在体外和体内的乙醇代谢率之间的差异可能取决于多种因素，包括竞争底物的存在下，pH值的差异，乙醇的肝外代谢，在肝脏和其他区域的血流变化，以及线粒体的NADH再氧化率的差异。最后一个可能是特别重要的适应性增加乙醇代谢后，慢性乙醇摄入。同时，经常伴随乙醇摄入的肝损伤或营养不良往往会降低ADH活性，因此对乙醇代谢的最终影响反映了相反趋势的平衡。
乙醇的代谢效应至少有三种不同类型：由乙醇本身的乙醇化产生的代谢物库和辅因子的改变引起的效应，由继发于中毒状态的神经内分泌紊乱引起的效应，以及由乙醇对特定细胞和过程的药理作用直接产生的效应。几乎在新陈代谢的每一个主要领域，这些不同类型的影响都有不同程度的贡献。许多关于乙醇代谢效应的明显分歧来自实验条件的差异，这导致这些因素的相对贡献有所不同。
第一种类型的影响，由乙醇代谢，已被研究得最深入。基本作用是肝细胞的细胞质和线粒体内的NADH：NAD+比率增加。这反过来又影响丙酮酸和草酰乙酸的可用性，从而在脂肪酸和其他底物的线粒体氧化、代谢和碳水化合物利用中引起广泛的一系列干扰。此外，核苷酸比例的变化直接影响氨基酸、生物胺、甘油、碳水化合物、卟啉和其他类别化合物代谢中涉及的许多其他NAD+依赖性反应。最后，在乙醇氧化过程中离开肝脏的大量乙酸盐、乳酸盐和脂质以及少量乙醛对其他组织的代谢产生间接影响。
第二类影响与中毒程度有关，研究得不那么透彻。交感神经和肾上腺髓质反应参与了大剂量乙醇引起的肝糖原分解，并可能参与了外周脂肪组织中脂肪酸的动员，这在单次大剂量乙醇后的肝脂肪变性中发挥了重要作用。通过各种器官的血液流动中的缺氧和紊乱可能是乙醇本身代谢及其对其他物质代谢的影响的大部分变异性的原因。
第三类效应是由乙醇的直接药理作用引起的，尽管它们可能被证明具有相当大的意义，但在所有效应中研究得最少。非常不完整的证据表明，乙醇可能会减少氨基酸在肝脏，胃肠道和其他地方的主动运输。它还可能对肝脏中脂蛋白的合成和胞吐作用、肾小管转运机制以及线粒体和细胞膜的渗透性等过程产生直接影响。所有这些，如果得到证实，将对新陈代谢产生重要影响。
由于体内乙醇氧化的特殊动力学，第一种类型的影响在体液中低浓度乙醇时占主导地位，而第二种和第三种类型的影响在较高浓度时变得越来越重要。在解释或预测任何给定条件下乙醇的代谢后果时，必须考虑到这种变化以及慢性乙醇摄入期间可能发生的营养失衡和肝脏病理学的复杂因素。
Despite a large amount of research on the metabolism of ethanol in the past decade, the picture has not changed radically with respect to the routes of this metabolism and the factors which control it. Catalase can certainly oxidize ethanol in vitro, and potential H22-generating systems exist within the cell, but no clear evidence has so far been presented to support the idea that ethanol is metabolized by a catalase system in vivo. Similarly, hepatic microsomal enzymes can oxidize ethanol in vitro by a reaction involving NADPH and oxygen (MEOS), but a substantial body of evidence suggests that this reaction plays no significant role in vivo, after either single or repeated administration of ethanol. Increase in MEOS activity after chronic ethanol intake is a reflection of increased smooth endoplasmic reticulum in the liver cell, but this may be related to the effect of ethanol on lipid metabolism rather than to the metabolism of ethanol itself.
Miscellaneous pathways involving esterification or condensation of ethanol with glucuronate, fatty acids or other substances, play a quantitatively trivial role in ethanol metabolism. The significance of these reactions lies in the interaction between ethanol and other substances which may compete for the same metabolic pathways.
Alcohol dehydrogenase (ADH) seems unquestionably the most important enzyme in the oxidation of ethanol. It probably detoxifies the small amounts of ethanol produced in the gastrointestinal tract, yet its kinetic properties suggest that its major role in vivo involves some other substrate than ethanol. Indeed, ADH appears to be a group of enzymes, each of which may have a different primary role in vivo. The discrepancy between ADH activity measured in vitro and the rate of ethanol metabolism in vivo probably depends upon a variety of factors including the presence of competing substrates, differences in pH, extrahepatic metabolism of ethanol, changes in hepatic and other regional blood flows, and differences in rate of mitochondrial reoxidation of NADH. The last may be particularly important in relation to adaptive increases in ethanol metabolism after chronic ethanol ingestion. At the same time liver damage or malnutrition, which frequently accompanies ethanol intake, tends to reduce the ADH activity so that the final effect on ethanol metabolism reflects a balance of opposing tendencies.
The metabolic effects of ethanol are of at least three different types: those resulting from alterations in metabolite pools and cofactors produced by the etabolism of ethanol itself, those resulting from neuroendocrine disturbances secondary to the state of intoxication, and those produced directly by the pharmacological action of ethanol on specific cells and processes. In almost every major area of metabolism these various types of effect contribute in different degrees. Many of the apparent disagreements concerning the metabolic effects of ethanol arise from differences in experimental conditions, which cause the relative contributions of these factors to vary.
Effects of the first type, resulting from ethanol metabolism, have been studied most intensively. The fundamental effect is the increase in NADH: NAD+ ratio within the cytoplasm and mitochondria of the liver cell. This in turn affects the availability of pyruvate and oxaloacetate, thus bringing about a wide-ranging series of disturbances in mitochondrial oxidation of fatty acids and other substrates, gluconeogenesis and carbohydrate utilization. In addition, the change in nucleotide ratio directly affects many other NAD+-dependent reactions involved in metabolism of amino acids, biogenic amines, glycerol, carbohydrates, porphyrins and compounds of other classes. Finally, the large amounts of acetate, lactate and lipids, and the smaller amounts of acetaldehyde, which leave the liver during ethanol oxidation produce indirect effects on the metabolism of other tissues.
Effects of the second type, related to the degree of intoxication, have been much less thoroughly studied. Sympathetic and adrenomedullary responses are involved in hepatic glycogenolysis produced by large doses of ethanol, and probably in the mobilization of fatty acids from peripheral adipose tissue which appears to play an important role in hepatic steatosis after a single large dose of ethanol. Hypoxia and disturbances in blood flow through various organs may account for much of the variability in metabolism of ethanol itself, as well as in its effects on metabolism of other substances.
Effects of the third type, resulting from a direct pharmacological action of ethanol, have been the least well explored of all, even though they may prove to be of considerable significance. Very incomplete evidence suggests that ethanol may reduce active transport of amino acids in the liver, gastrointestinal tract and elsewhere. It may also have a direct effect on processes involved in synthesis and exocytosis of lipoproteins in the liver, on renal tubular transport mechanisms, and on permeability of mitochondrial and cell membranes. All of these, if verified, would have important implications for metabolism.
Because of the peculiar kinetics of ethanol oxidation in vivo, effects of the first type predominate at low concentrations of ethanol in body fluids, while those of the second and third types become progressively more important at higher concentrations. This variation, together with the complicating factors of nutritional imbalance and hepatic pathology which may occur during chronic ethanol ingestion, must be taken into account in explaining or predicting the metabolic consequences of ethanol under any given set of conditions.