Alcohol tolerance and human genetic diversity

Two key enzymes.

The chemical name for alcohol is ethanol (CH3CH2OH). The body processes and eliminates ethanol in separate steps. Chemicals called enzymes help to break apart the ethanol molecule into other compounds (or metabolites), which can be processed more easily by the body. Some of these intermediate metabolites can have harmful effects on the body.

Most of the ethanol in the body is broken down in the liver by an enzyme called alcohol dehydrogenase (ADH), which transforms ethanol into a toxic compound called acetaldehyde (CH3CHO), a known carcinogen. However, acetaldehyde is generally short-lived; it is quickly broken down to a less toxic compound called acetate (CH3COO-) by another enzyme called aldehyde dehydrogenase (ALDH). Acetate then is broken down to carbon dioxide and water, mainly in tissues other than the liver.

Alcohol metabolism and cancer

Alcohol consumption can contribute to the risk for developing different cancers, including cancers of the upper respiratory tract, liver, colon or rectum, and breast (19). This occurs in several ways, including through the toxic effects of acetaldehyde (20).


Ironically, the very genes that protect some people from alcoholism may magnify their vulnerability to alcohol-related cancers. The International Agency for Research on Cancer (21) asserts that acetaldehyde should be classified as a carcinogen. Acetaldehyde promotes cancer in several ways—for example, by interfering with the copying (i.e., replication) of DNA and by inhibiting a process by which the body repairs damaged DNA (5). Studies have shown that people who are exposed to large amounts of acetaldehyde are at greater risk for developing certain cancers, such as cancers of the mouth and throat (5). Although these individuals often are less likely to consume large amounts of alcohol, Seitz and colleagues (5) suggest that when they do drink their risk for developing certain cancers is higher than drinkers who are exposed to less acetaldehyde during alcohol metabolism. Many heavy drinkers do not develop cancer, and some people who drink only moderately do develop alcohol-related cancers. Research suggests that just as some genes may protect individuals against alcoholism, genetics also may determine how vulnerable an individual is to alcohol’s carcinogenic effects (5).
Acetaldehyde is not the only carcinogenic byproduct of alcohol metabolism. When alcohol is metabolized by CYP2E1, highly reactive, oxygen-containing molecules—or reactive oxygen species (ROS)—are produced. ROS can damage proteins and DNA or interact with other substances to create carcinogenic compounds (22).

Our tools of epidemiology and meta-analysis do work when there is an increased RR of cancer;

THE GENETICS BEHIND METABOLISM

Regardless of how much a person consumes, the body can only metabolize a certain amount of alcohol every hour (2). That amount varies widely among individuals and depends on a range of factors, including liver size (1) and body mass.

In addition, research shows that different people carry different variations of the ADH and ALDH enzymes. These different versions can be traced to variations in the same gene. Some of these enzyme variants work more or less efficiently than others; this means that some people can break down alcohol to acetaldehyde, or acetaldehyde to acetate, more quickly than others. A fast ADH enzyme or a slow ALDH enzyme can cause toxic acetaldehyde to build up in the body, creating dangerous and unpleasant effects that also may affect an individual’s risk for various alcohol-related problems—such as developing alcoholism.

The type of ADH and ALDH an individual carries has been shown to influence how much he or she drinks, which in turn influences his or her risk for developing alcoholism (11). For example, high levels of acetaldehyde make drinking unpleasant, resulting in facial flushing, nausea, and a rapid heart beat. This “flushing” response can occur even when only moderate amounts of alcohol are consumed. Consequently, people who carry gene varieties for fast ADH or slow ALDH, which delay the processing of acetaldehyde in the body, may tend to drink less and are thus somewhat “protected” from alcoholism (although, as discussed later, they may be at greater risk for other health consequences when they do drink).

Genetic differences in these enzymes may help to explain why some ethnic groups have higher or lower rates of alcohol-related problems. For example, one version of the ADH enzyme, called ADH1B*2, is common in people of Chinese, Japanese, and Korean descent but rare in people of European and African descent (12). Another version of the ADH enzyme, called ADH1B*3, occurs in 15 to 25 percent of African Americans (13). These enzymes protect against alcoholism (14) by metabolizing alcohol to acetaldehyde very efficiently, leading to elevated acetaldehyde levels that make drinking unpleasant (15). On the other hand, a recent study by Spence and colleagues (16) found that two variations of the ALDH enzyme, ALDH1A1*2 and ALDH1A1*3, may be associated with alcoholism in African-American people.

Although these genetic factors influence drinking patterns, environmental factors also are important in the development of alcoholism and other alcohol-related health consequences. For example, Higuchi and colleagues (17) found that as alcohol consumption in Japan increased between 1979 and 1992, the percentage of Japanese alcoholics who carried the protective ADH1B*2 gene version increased from 2.5 to 13 percent. Additionally, despite the fact that more Native American people die of alcohol-related causes than do any other ethnic group in the United States, research shows that there is no difference in the rates of alcohol metabolism and enzyme patterns between Native Americans and Whites (18). This suggests that rates of alcoholism and alcohol-related problems are influenced by other environmental and/or genetic factors.

https://pubs.niaaa.nih.gov/publications/aa72/aa72.htm

C2H5OH metabolism

Where? Alcohol is metabolized in the body mainly by the liver. The brain, pancreas, and stomach also metabolize alcohol.