Alcohol, Chemistry and You
Metabolism of Ethyl Alcohol in the Body
Dr. Bill Boggan

Problems

Case Study
 

Combustion and Ethanol

Ethanol burns with a blue flame. We know the reaction is spontaneous and exothermic. But we also know that ethanol is stable in the bottle. It will last for a long, long, time without undergoing this spontaneous oxidation.

And then we drink it and ethanol is converted to acetic acid. This oxidation takes place at 37 ^o C under conditions that would not seem to allow oxidation.

That's what enzymes do. Enzymes are catalysts that lower the activation energy for chemical processes so that reactions take place at lower temperatures.

Enzymes are active because of their shape. Specific enzymes allow binding of the molecules, they bring the substances together, nestle them comfortably, so that the slightest vibration causes the spontaneous, but otherwise unobtainable reaction to proceed.

Alcohols and Acronyms

The enzyme alcohol dehydrogenase is a high molecular weight protein molecule. Proteins are made up of sequences of amino acids folded into special shapes that catalyze reactions. We express the enzymes by acronym rather than structure because our focus is on the ethanol chemistry, not the enzyme. But this "mixed" representation is typical of what we can expect in chemistry. In the same expression we have a formula and an acronym!

More than 90% of the ethyl alcohol that enters the body is completely oxidized to acetic acid. This process occurs primarily in the liver. The remainder of the alcohol is not metabolized and is excreted either in the sweat, urine, or given off in one’s breath. The latter provides the basis of the breathalizer test used in law enforcement and is the reason one can smell alcohol on the breath of someone who has been drinking recently. There are several routes of metabolism of ethyl alcohol in the body. The major pathways involve the liver and in particular the oxidation of ethyl alcohol by alcohol dehydrogenase (ADH). Playing a role, particularly at higher alcohol concentrations is the oxidation of alcohol by the microsomal (small spherical vesicles) - cytochrome P450 system (MEOS) system. In addition to these routes, there is catalase-dependent oxidation of ethyl alcohol and oxidation of it by the stomach when it is first ingested. These latter two routes of metabolism are minor in comparison to the ADH and MEOS systems.

As mentioned above perhaps the major route of metabolism of ethyl alcohol is its oxidation in the liver catalyzed by the cytosolic enzyme alcohol dehydrogenase (ADH). It catalyzes the following reaction:

CH₃CH₂OH + NAD⁺ -> CH₃CHO + NADH + H⁺.

This reaction produces acetaldehyde, a highly toxic substance. ADH has broad specificity, catalyzing various alcohols and steroids and catalyzing the oxidation of fatty acids. It also is not a solitary enzyme in that there are five different ADH genes, two of which ADH2 and ADH3 shown polymorphism (variations). Of importance is the fact that the ability of people to oxidize ethyl alcohol is dependent upon the genetic makeup of the individual. People with alleles (types) of ADH2 and ADH3 may protect those having these genes from developing alcoholism. These genes are common in the Asian population and convert alcohol to acetaldehyde more rapidly than normal. Because of this increased production of acetaldehyde, this toxic compound builds up and makes people who drink too much uncomfortable and ill. Therefore, these carries are discouraged from consuming large amount of alcohol.

A similar situation is found in the second step of ethanol metabolism, which is catalyzed by acetaldehyde dehydrogenase. This enzyme converts acetaldehyde to acetic acid, which is a normal metabolite in humans and hence is non toxic. The past use of Antabuse as a possible deterrent to drinking was based on the ability of Antabuse to inhibit the action of acetaldehyde dehydrogenase, thus slow down or stop the destruction of acetaldehyde. If one drank after taking Antabuse, the person got very ill. It turns out that certain individuals, again common in Asians, have a defective aldehyde dehydrogenase gene, ALDH2, in that it doesn’t metabolize acetaldehyde as rapidly as normal. Thus, a person who drinks too much builds up acetaldehyde in their system and feels bad or is sick. This manifests in Asians with the defected ALDH gene as a facial flush as they drink. These responses discourage drinking, thus preventing the development of alcohol abuse, dependence, and alcoholism.

Another system in the liver which oxidizes ethanol via the enzyme cytochrome P450IIE1 (CYP2E1) is called the MEOS system. The reaction catalyzed by MEOS is:

CH₃CH₂OH + NADPH + O₂ -> CH₃CHO + NADP⁺ + H₂O.

Though of minor significance in comparison to ADH metabolism of ethanol, the MEOS system seems to play an increasingly important role at higher concentrations of ethanol. It is not surprising that there are variations in the P450E1 enzyme which lead to differences in the rate of ethanol metabolism. This may have implications for tissue damage from ethanol, particular in the liver.

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