Once ethanol is in the circulation, it reaches all tissues in the body, including the brain, where it causes intoxication. Our bodies are designed to terminate the action of drugs, including alcohol, so that the intoxication doesn’t persist when a person stops drinking. In fact, the body starts eliminating ethanol before it even gets into the general circulation!
Ethanol moves from the GI tract to the liver
When a person consumes alcohol, the first place that the alcohol goes after it leaves the GI tract is the liver (Figure 1.10). Once it enters the capillaries surrounding the stomach and small intestines, the capillaries lead to the portal vein, which enters the liver and branches out once again into capillaries. Ethanol diffuses from the capillaries (with the concentration gradient) into the nearby hepatic cells (the major cells of the liver).
In the hepatic (liver) cells, some of the ethanol is converted, or detoxified by enzymes to inactive products. This process is called metabolism, and the products are called metabolites.
Figure 1.10 Watch the alcohol (in green) move from the GI tract through the portal vein to the liver, where it is metabolized.
Alcohol is metabolized in 2 stages
Metabolism of drugs by liver enzymes serves two purposes. First, metabolism is a way of “turning off” the action of a drug. In general, metabolites have less biological activity relative to the parent compound, although there are some exceptions to this rule, as we will see with ethanol.
Second, metabolism helps to convert the drug into a more polar (water-soluble) form so it can be carried in the bloodstream to the kidneys, where it is excreted in the urine (water-based). During metabolism, the enzymes are catalysts; they help speed up the reactions; however, the metabolism speed is different for different people, based on their genetics.
Review enzymes as catalysts.
Stage 1: Ethanol to acetaldehyde
Although some alcohol is metabolized in the stomach, the primary site of metabolism is in the liver. The cytoplasm of liver cells contain an enzyme called alcohol dehydrogenase (ADH) that catalyzes the oxidation of ethanol to acetaldehyde (Figure 1.11). The oxidation occurs when ethanol binds to a site on the ADH enzyme and loses some electrons in the form of H atoms. Actually ethanol gives up 2 H atoms to another molecule that also binds to ADH. In this case, the recipient molecule of the electrons is called a coenzyme. Without the coenzyme, the ADH enzyme won’t work very well.
The primary metabolite of ethanol oxidation, is acetaldehyde. This compound is relatively toxic, and it is responsible for alcohol-related facial flushing, headaches, nausea, and increased heart rate. These toxic effects of acetaldehyde contribute to the alcohol “hang-over” that persists for a significant time after drinking. Acetaldehyde is also carcinogenic (i.e., it can cause cancer). If too much acetaldehyde builds up, it increases the risk of stomach and intestinal cancer. But stage 2 metabolism helps lessen this risk.
Figure 1.11 Ethanol is oxidized by ADH to acetaldehyde in the cytoplasm, and then the acetaldehyde is oxidized by ALDH in the mitochondria to acetic acid.
Stage 2: Acetaldehyde to acetic acid
The body has a natural way to “get rid” of the acetaldehyde…remember, this is toxic to the body. There is a second liver enzyme, present in the mitochondria, called acetaldehyde dehydrogenase (ALDH). ALDH metabolizes acetaldehyde to acetic acid (Figure 1.11), which is inactive. The acetic acid is eventually converted in the cell into carbon dioxide and water. Some people do not have the ability to metabolize acetaldehyde very well. When they drink alcohol, acetaldehyde accumulates in the blood and makes them feel sick. They have facial flushing, headaches, nausea, vomiting, and a rapid heart rate. The reason that some people can’t metabolize acetaldehyde very well is because they have a form of ALDH that has a mutation in the gene that codes for it. The form of ALDH that has the mutation is very inefficient at metabolizing acetaldehyde. People with this genetic mutation do not like to drink alcohol because it makes them feel bad. They are also at higher risk of getting gastric cancers.
Learn more about different forms of ALDH and ADH in various populations.
Learn more about oxidation.
Overwhelming the alcohol metabolizing enzymes
There is enough ADH present in a person’s liver to metabolize all the alcohol molecules from one drink quite efficiently within an hour or two. The rate of metabolism remains constant during continued drinking. Why is this important? As the consumption of alcohol increases, there just aren’t enough ADH molecules (in the liver or the stomach) to metabolize the extra alcohol quickly enough. So, alcohol begins to accumulate in the bloodstream, giving an increased blood alcohol concentration (BAC) that leads to intoxication. In other words, when the metabolism of ethanol is limited by the number of ADH enzyme molecules present, it proceeds at a rate that is independent of the amount of alcohol in the bloodstream…and then alcohol accumulates in the bloodstream (Figure 1.12)
Figure 1.12 Watch how alcohol is metabolized in the liver when it binds to the enzyme, ADH. The number of ADH enzyme molecules is limited. With more than one drink of alcohol, the enzymes become saturated with ethanol molecules binding to it. So the rest of the alcohol molecules accumulate and leave the liver to go back into the bloodstream.
Alcohol that is not metabolized on its first passage through the liver continues to circulate throughout the body as an active drug. [Trivia! It takes about a minute for molecules to circulate through the bloodstream in a single pass.] Thus, ultimately, only a small fraction of the ingested alcohol escapes metabolism. This small amount of alcohol (5-10%) is eliminated unchanged in the breath as vapor or in the urine.
Learn more about the elimination of alcohol in the breath.