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Ethanol metabolism

Ethanol metabolismAbsorption, distribution, and elimination. In a healthy man, about 100 mg of ethanol per kilogram of body weight is eliminated in an hour. Heavy alcohol consumption for years may increase the rate of ethanol elimination up to 100%.

Ethanol is absorbed from the gastrointestinal tract, especially the duodenum and jejunum (70%-80%), by simple diffusion because of its small molecular size and low solubility in lipids. The rate of absorption is decreased by delayed gastric emptying and by the presence of intestinal contents. Food delays gastric absorption, producing a slower rise and lower peak value of blood alcohol in fed than in fasting patients.

The systemic distribution of alcohol is very rapid. In organs with a rich blood supply, such as the brain, lungs, and liver, alcohol rapidly equilibrates with the blood. Alcohol is poorly lipid-soluble. At room temperature, tissue lipids take up only 4% of the quantity of alcohol dissolved in a corresponding volume of water. In an obese person, therefore, the same amount of alcohol per unit of weight gives a higher blood alcohol concentration than in a thin person. The mean volume of distribution of ethanol is less in women than in men, resulting in higher peak blood concentrations and greater mean areas under the ethanol concentration-time curves.

In humans, less than 1% is excreted in the urine, 1% to 3% via the lungs, and 90% to 95% as carbon dioxide after it is oxidized in the liver.

TABLE. ALCOHOL CONTENT OF VARIOUS BEVERAGES
Beverage Alcohol
Concentration*
(g/100 mL)
Alcohol in
Standard Measures
Beer 3.9 13.3 g; 12-oz bottle/can
Red wine 9.5 11.0 g/glass; 71 g/bottle
RosГ© 8.7 10.0 g/glass; 65 g/bottle
White wine, dry 9.1 10.0 g/glass; 64 g/bottle
White wine, medium 8.8 10.0 g/glass; 62 g/bottle
White wine, sweet 10.2 11.0 g/glass; 71 g/bottle
White wine, sparkling 9.9 11.0 g/glass; 74 g/bottle
Port 15.9 124 g/bottle
Sherry, dry 15.7 123 g/bottle
Sherry, medium 14.8 115 g/bottle
Sherry, sweet 15.6 122 g/bottle
Vermouth, dry 13.9 122 g/bottle
Vermouth, sweet 13.0 100 g/bottle
Cherry brandy 19.0 148 g/bottle
Hard liquor 70%
(brandy, gin, whiskey)
31.7 240 g/bottle; 7.5 g/single-shot
*Percentage alcohol x 0.078 = g alcohol/100 mL.
Key: 1 fl oz = 30 mL; 1 pint = 470 mL; 1 wine bottle = 757 mL.

Chemical metabolism

Alcohol dehydrogenase. Although most of the ingested ethanol is metabolized by the liver, other tissues such as the stomach, intestines, kidney, and bone marrow cells oxidize ethanol to a small extent. There is an alcohol dehydrogenase  present in the mucosa of the stomach, jejunum, and ileum, which results in a considerable first-pass metabolism of alcohol.

The gastric alcohol dehydrogenase activity is less in women than in men and decreases with chronic alcoholism. Concomitant ingestion of histamine-2 blockers such as cimetidine and ranitidine with ethanol decreases gastric alcohol dehydrogenase activity. This effect has not been noted with famotidine.

In the liver, the main pathway for ethanol metabolism is by its oxidation to acetaldehyde by alcohol dehydrogenase. Alternative pathways of oxidation in other subcellular compartments are also present. Multiple molecular forms of alcohol dehydrogenase exist, and at least three different classes have been described on the basis of structure and function. Various alcohol dehydrogenase forms appear in different frequencies in different racial populations. This polymorphism may explain, in part, individual variation in the rate of acetaldehyde production and first-pass elimination.

The hepatic metabolism of ethanol proceeds in three basic steps. First, ethanol is oxidized within the hepatocyte cytosol to acetaldehyde. Second, acetaldehyde is oxidized to acetate via catalysis mainly by aldehyde dehydrogenase in the mitochondria. Third, acetate aldehyde dehydrogenase is released into blood and is oxidized by peripheral tissues to carbon dioxide and water.

When ethanol is oxidized to acetaldehyde via alcohol dehydrogenase, nicotinamide-adenine dinucleotide  is required as a cofactor and is reduced to NADH during the reaction, resulting in an increase in the liver of the NADH/nicotinamide-adenine dinucleotide ratio. This increase in the redox state of the liver has serious metabolic effects such as inhibition of hepatic gluconeogenesis, impairment of fatty-acid oxidation, decrease in citric acid cycle activity, and increase in conversion of pyruvate to lactic acid resulting in lactic acidosis.

The microsomal ethanol oxidizing system is located in the endoplasmic reticulum of the hepatocyte. It is a cytochrome P-450-, NADPH- (reduced nicotinamide-adenine-dinucleotide phosphate), and oxygen-dependent enzyme system that oxidizes ethanol to acetaldehyde. Because chronic consumption of ethanol leads to the proliferation of the endoplasmic reticulum, the activity of the microsomal ethanol oxidizing system is also increased (induction). However, its quantitative contribution to the total ethanol metabolism is still controversial. The current nomenclature for microsomal ethanol oxidizing system is P45011E1. In addition to ethanol, this enzyme system oxidizes other alcohols, carbon tetrachloride (CCl4), and acetaminophen (Tylenol).

Aldehyde dehydrogenase rapidly metabolizes acetaldehyde to acetate. Multiple molecular forms of aldehyde dehydrogenase have been demonstrated. Two major hepatic aldehyde dehydrogenase isoenzymes (I and II) exist in humans. The mitochondrial isoenzyme (aldehyde dehydrogenase I) has been reported to be missing in about 50% of liver specimens in Japanese people. The deficiency of aldehyde dehydrogenase I in Asians has several metabolic and clinical consequences.

Change in hepatic redox state. When ethanol is oxidized to acetaldehyde in the hepatocyte cytosol via alcohol dehydrogenase, nicotinamide-adenine dinucleotide is required as a cofactor. nicotinamide-adenine dinucleotide is reduced to NADH. Also, aldehyde dehydrogenase-mediated conversion of acetaldehyde to acetate requires nicotinamide-adenine dinucleotide conversion of NADH in the mitochondria. Thus, both the cytosolic and mitochondrial redox states are altered. This effect is manifested by respective increases of both liver and blood lactate to pyruvate and of ОІ-hydroxybutyrate to acetoacetate ratios. This state leads to inhibition of hepatic gluconeogenesis, fatty-acid oxidation, and citric acid cycle activity, which may clinically exhibit as fatty liver, hypoglycemia, and lactic acidosis.

Alterations in metabolism of ethanol, acetaldehyde, and acetate during chronic alcohol consumption. Chronic ethanol consumption enhances ethanol clearance except in the presence of clinically significant liver damage or severe food restriction. This effect is attributed to increased alcohol dehydrogenase activity, microsomal ethanol oxidizing system activity, a hypermetabolic state in the liver, and possible increased mitochondrial reoxidation of NADH, which is the rate-limiting step in ethanol elimination and metabolism. The explanation for increased ethanol elimination by corticosteroids is the induced increase in NADH conversion to nicotinamide-adenine dinucleotide as a result of steroid-induced gluconeogenesis.

In healthy people, almost all the acetaldehyde formed during ethanol oxidation is effectively oxidized in the liver. However, detectable concentrations of acetaldehyde have been found in the peripheral blood of chronic alcoholics and in Asians, who experience alcohol-related flushing. The unusually high blood acetaldehyde levels found in severely intoxicated, chronic alcoholics are thought to result from an increased rate of ethanol oxidation of alcohol dehydrogenase and a decrease in the liver aldehyde dehydrogenase activity associated with both liver injury and chronic ethanol consumption.

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