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Ethanol has been a part of the human diet for centuries. However, its consumption in excess can result in a number of health problems, most notably liver damage. What is the biochemical basis of these health problems?
Ethanol cannot be excreted and must be metabolized, primarily by the liver. This metabolism occurs by two pathways. The first pathway comprises two steps. The first step, catalyzed by the enzyme alcohol dehydrogenase, takes place in the cytoplasm:
The second step, catalyzed by aldehyde dehydrogenase, takes place in mitochondria:
Note that ethanol consumption leads to an accumulation of NADH. This high concentration of NADH inhibits gluconeogenesis by preventing the oxidation of lactate to pyruvate. In fact, the high concentration of NADH will cause the reverse reaction to predominate, and lactate will accumulate. The consequences may be hypoglycemia and lactic acidosis.
The NADH glut also inhibits fatty acid oxidation. The metabolic purpose of fatty acid oxidation is to generate NADH for ATP generation by oxidative phosphorylation, but an alcohol consumer's NADH needs are met by ethanol metabolism. In fact, the excess NADH signals that conditions are right for fatty acid synthesis. Hence, triacylglycerols accumulate in the liver, leading to a condition known as “fatty liver.”
The second pathway for ethanol metabolism is called the ethanolinducible microsomal ethanol-oxidizing system (MEOS). This cytochrome P450-dependent pathway (Section 26.4.2) generates acetaldehyde and subsequently acetate while oxidizing biosynthetic reducing power, NADPH, to NADP+. Because it uses oxygen, this pathway generates free radicals that damage tissues. Moreover, because the system consumes NADPH, the antioxidant glutathione cannot be regenerated (Section 20.5), exacerbating the oxidative stress.
What are the effects of the other metabolites of ethanol? Liver mitochondria can convert acetate into acetyl CoA in a reaction requiring ATP. The enzyme is the thiokinase that normally activates short-chain fatty acids.
However, further processing of the acetyl CoA by the citric acid cycle is blocked, because NADH inhibits two important regulatory enzymes— isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. The accumulation of acetyl CoA has several consequences. First, ketone bodies will form and be released into the blood, exacerbating the acidic condition already resulting from the high lactate concentration. The processing of the acetate in the liver becomes inefficient, leading to a buildup of acetaldehyde. This very reactive compound forms covalent bonds with many important functional groups in proteins, impairing protein function. If ethanol is consistently consumed at high levels, the acetaldehyde can significantly damage the liver, eventually leading to cell death.
Liver damage from excessive ethanol consumption occurs in three stages. The first stage is the aforementioned development of fatty liver. In the second stage—alcoholic hepatitis—groups of cells die and inflammation results. This stage can itself be fatal. In stage three—cirrhosis—fibrous structure and scar tissue are produced around the dead cells. Cirrhosis impairs many of the liver's biochemical functions. The cirrhotic liver is unable to convert ammonia into urea, and blood levels of ammonia rise. Ammonia is toxic to the nervous system and can cause coma and death. Cirrhosis of the liver arises in about 25% of alcoholics, and about 75% of all cases of liver cirrhosis are the result of alcoholism. Viral hepatitis is a nonalcoholic cause of liver cirrhosis.