alcohol dehydrogenase isoenzymes found in human tissue is unparalleled among mammalian tissues; up to 17 isoenzymes are identifiable in human liver. The alcohol dehydrogenase isoenzymes vary dramatically in their activity on ethanol. Different ẞ subunit forms of alcohol dehydrogenase have been found in different racial groups. Whereas the alcohol dehydrogenase isoenzyme known as ẞ1 occurs predominantly in the Caucasian population, B2 appears in 65 percent of the Asian population, and ẞ3 occurs in 15 percent of the African-American population. These ẞ subunits differ by only a single amino acid substitution, which produces isoenzymes that vary substantially in their ability to oxidize ethanol. Individuals with the ẞ2 isoenzymes (predominantly Asians) appear to oxidize ethanol faster than those with the ẞi isoenzyme (predominantly Caucasians). These different rates lead to variations in acetaldehyde concentrations that may contribute to tissue injury.

The immediate product of alcohol oxidation, acetaldehyde, is further metabolized (oxidized) to acetic acid by a class of enzymes known as aldehyde dehydrogenases. Recent research has shown that alcohol itself may interfere with the activity of aldehyde dehydrogenase.

Women may metabolize ethanol less efficiently than men do, thereby producing higher BACS in a shorter time. The reason for this difference is not known, but the difference may lead to women being more vulnerable to alcoholinduced liver damage. The intake of aspirin (acetylsalicylic acid) or cimetidine (a drug used to inhibit gastric secretion in individuals with ulcers) in conjunction with ethanol enhances BACS; this effect is believed to be due to the inhibition of alcohol dehydrogenase isoenzymes in the stomach.

Although alcohols are oxidized primarily by alcohol dehydrogenases, some alcohols may also be oxidized within a subcellular complex of the liver cell called the endoplasmic reticulum. The complex, known as the MEOS, contains cytochrome P450 IIE1.

The immediate product of alcohol oxidation, acetaldehyde, is further metabolized (oxidized)

to acetic acid by a class of enzymes known as aldehyde dehydrogenases. Although aldehyde dehydrogenases are found in many tissues, most oxidation of acetaldehyde occurs at the major site of the product's synthesis, the liver. Four distinct aldehyde dehydrogenase isoenzymes have been purified from human liver. A genetic variant of one of these forms, the mitochondrial aldehyde dehydrogenase isoenzyme, appears in about 50 percent of the Asian population. The variant has a drastically reduced enzyme activity. In those individuals producing the inactive variant-predominantly Asians-circulating acetaldehyde levels can be 20 times higher than in individuals who produce the active isoenzyme. The effects of the high acetaldehyde concentration include facial flushing, palpitations, dizziness, and nausea. The adverse side effects among these individuals probably deter them from heavy alcohol consumption.

Recent research has shown that alcohol itself may interfere with the activity of aldehyde dehydrogenase. Alcohol has been found to slow the movement of large proteins across the mitochondrial membrane. Because aldehyde dehydrogenase is one of the enzymes that must be transported from the cytoplasm into the mitochondria, impaired membrane transport of this enzyme may result in less efficient acetaldehyde oxidation and the subsequent risk of greater liver injury from increased acetaldehyde levels.

The oxidation of alcohol and acetaldehyde may affect other metabolic processes. Alcohol use may divert normal lipid metabolism; one example is the production of lipid species known as fatty acid ethyl esters.

Ethylcocaine, which is made from cocaine and ethanol, has been found in individuals who use both drugs simultaneously. This unnatural compound, which appears to be pharmacologically active, may enhance the toxicity of cocaine and alcohol co-use.

Excess acetaldehyde may combine with protein to form acetaldehyde adducts that can disrupt normal protein functioning. One such protein that may be modified by acetaldehyde is tubulin, which is important in protein trafficking, that is, the movement of extracellular protein, such as albumin, outside the cell. Acetaldehyde adducts of tubulin may hamper protein trafficking and lead to protein accumulation in the cell. Acetaldehyde adducts of rat membrane phospholipids have also been found with chronic ethanol intake; these surface-exposed adducts may initiate antibody production.

Excessive alcohol use may cause deficiencies in a number of vitamins, including B1 (thiamine), A, folate, D, B6, and E. Individuals who chronically drink alcohol may lose weight despite being well fed; weight loss among alcoholic women appears to be greater than that among alcoholic men, but the reason is not clear. These weight losses indicate that more energy is expended than can be obtained from ethanol as a food source, though the mechanisms underlying the losses have not been clearly defined.

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