Pathways of Alcohol Metabolism : ADH Pathway, Microsomal Ethanol-Oxidizing System

by National Institute of Health

(Page 5 of 7)

The ADH Pathway

The ADH pathway, which converts alcohol to the toxic substance acetaldehyde in a reaction that releases hydrogen atoms, is responsible for most of the alcohol breakdown in liver cells. However, how fast alcohol is broken down by this pathway depends, at least in part, on nutritional factors. For example, low-protein diets reduce the levels of ADH in the liver, lowering the rate of alcohol breakdown both in humans and in laboratory animals. Prolonged fasting also has been shown to decrease the rate of alcohol breakdown in isolated rat liver cells. These observations suggest that for any given alcohol dose, malnourished alcoholics break down the alcohol more slowly and therefore develop higher blood alcohol levels, and sustain them longer, than well-nourished subjects. Because the effects of alcohol on the body depend on blood alcohol levels, reduced alcohol degradation may lead to more severe damage to the liver and other organs.

Conversely, alcohol metabolism by the ADH pathway also may influence metabolic functions. As mentioned above, ADH-mediated breakdown of alcohol generates hydrogen atoms in addition to acetaldehyde. These hydrogen atoms interact with a molecule called nicotinamide adenine dinucleotide, converting it to reduced NAD. NADH, in turn, participates in many essential biochemical reactions in the cell, and in the process passes on its hydrogen to other molecules. For proper functioning of the cell, the ratio of NAD to NADH must be tightly controlled. When alcohol metabolism generates excess amounts of NADH, the cell can no longer maintain the normal NAD/NADH ratio. This altered NAD/NADH ratio may lead to several metabolic disorders. For example, elevated levels of NADH cause the formation of abnormally high levels of lactic acid, which in turn reduce the capacity of the kidney to excrete uric acid. Excessive uric acid in the body can exacerbate gout, a disorder characterized by extremely painful swelling of certain joints. Therefore, alcohol-induced increases in NADH levels and, subsequently, uric acid levels, which can be worsened by other alcohol-induced metabolic effects, may at least partly explain the common clinical observation that excessive alcohol consumption causes or aggravates attacks of gout.

In addition, increased NADH promotes the generation of the building blocks of fat molecules and reduces the breakdown of fats in the liver, thereby contributing to fat accumulation in that organ. Other alcohol-related mechanisms also contribute to fat accumulation in the liver, including: decreased excretion of fat-containing proteins from the liver. Release of fats from other tissues, which then are transported to the liver. Enhancement of the liver's uptake of fats circulating in the blood.

The resulting fatty liver is the earliest stage and the most common form of alcohol-induced liver disease.

In addition to contributing to the development of fatty liver, the increases in NADH levels resulting from the ADH-mediated breakdown of alcohol also may play a role in the formation of scar tissue that characterizes fibrosis, a more severe stage of liver disease. This relationship was suggested by the observation that a molecule that can capture hydrogen away from NADH completely prevents certain liver cells (stellate cells) from producing elevated levels of molecules that contribute to the formation of scar tissue.

The Microsomal Ethanol-Oxidizing System (MEOS)

After moderate alcohol consumption, most of the ingested alcohol is broken down by the ADH pathway described above. After chronic heavy alcohol consumption, the MEOS pathway of alcohol metabolism becomes more important. This pathway consists of several enzymes located in the liver microsomes - small spherical structures found in all cells. The MEOS has been investigated extensively because its activity increases substantially after long-term alcohol consumption and because it is important for the breakdown and elimination of other foreign molecules from the body, including certain medications. Therefore, activation of the MEOS after alcohol consumption may alter the breakdown of those medications and may contribute to harmful interactions between alcohol and those medications.

The primary component of the MEOS is the molecule cytochrome P450, which exists in several variants. The variant most important for alcohol metabolism is cytochrome P450 2E1 (CYP2E1). Studies using liver biopsies from people who recently had been drinking alcohol found that the levels of CYP2E1 were four times higher in these subjects than in control subjects who had not been drinking alcohol. In contrast, the levels of ADH in the liver did not change following alcohol consumption.

Enhanced CYP2E1 activity in response to chronic alcohol consumption (or other factors) probably contributes to the development of alcoholic liver disease. Alcoholics commonly suffer from a type of liver disease called steatohepatitis, which is an inflammation of the liver with concurrent fat accumulation in the liver. Steatohepatitis also is frequently found in people with diabetes and excessive or morbid obesity, even if they are not alcoholics. Studies have found that, in addition to breaking down alcohol, CYP2E1 also mediates certain steps in the metabolism of fatty acids as well as of chemicals called ketones (acetone) and that acetone, like alcohol, can stimulate CYP2E1 activity. Patients with diabetes or morbid obesity commonly have higher than normal levels of fatty acids and ketones. This observation suggests that, in nonalcoholics, steatohepatitis can be the end result of enhanced CYP2E1 activity caused by excess levels of ketones and fatty acids; in alcoholics, steatohepatitis can result from enhanced CYP2E1 activity caused by chronic heavy drinking.

Alcohol-induced activation of the MEOS also contributes to alcoholic liver disease through other mechanisms. For example, alcohol breakdown by CYP2E1 generates several types of highly reactive oxygen-containing molecules called reactive oxygen species (ROS). These ROS can damage liver cells by inactivating essential enzymes and altering the breakdown of fat molecules; higher ROS levels contribute to a condition called oxidative stress, which can cause liver cell damage. These ROS effects are exacerbated if the body's normal defense systems against this damage - antioxidants, such as glutathione (GSH) and vitamin E (α-tocopherol) - also are impaired. Alcohol and its metabolism have been shown to reduce the levels of both GSH and vitamin E. For example, the breakdown product of alcohol, acetaldehyde, lowers GSH levels in the liver. Furthermore, patients with cirrhosis have reduced amounts of vitamin E in the liver. Thus, alcohol metabolism through the MEOS can lead to liver damage both by generating harmful substances (the ROS) and by reducing the levels of protective substances (GSH).

About the Author

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