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Research Article

The Metabolism of Ethanol and Its Metabolic Effects

Rosemary D. Hawkins and H. Kalant
Pharmacological Reviews March 1972, 24 (1) 67-157;
Rosemary D. Hawkins
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H. Kalant
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Abstract

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 H202-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.

  • 1971, by The Williams & Wilkins Co.

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Pharmacological Reviews
Vol. 24, Issue 1
1 Mar 1972
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Research Article

The Metabolism of Ethanol and Its Metabolic Effects

Rosemary D. Hawkins and H. Kalant
Pharmacological Reviews March 1, 1972, 24 (1) 67-157;

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Research Article

The Metabolism of Ethanol and Its Metabolic Effects

Rosemary D. Hawkins and H. Kalant
Pharmacological Reviews March 1, 1972, 24 (1) 67-157;
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