To Drink or Not to Drink: A Deep Dive into Alcohol Metabolism

Alcohol use disorder (AUD), or alcoholism, is defined as an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. It's important to understand that sensitivity to alcohol and AUD are inversely related. In other words, if just one drink gets you drunk, you're likely to drink less.

Today we're going to talk about how alcohol is metabolized, some factors that affect how much any given drink will affect you, and explore how your genetics might protect you from addiction.

The stars of today's show are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are chiefly responsible for metabolizing the ethanol in your drink and eliminating it from your bloodstream.

ADH works by turning ethanol into acetaldehyde (a toxic metabolite), which ALDH then converts to acetic acid. These conversions require NAD+ to snag hydrogen from ethanol and acetaldehyde respectively. At blood pH levels, acetic acid loses the hydrogen on the hydroxyl group (OH) and becomes acetate (C₂H₃O₂⁻) which has a negative charge. Eventually acetate is oxidized to carbon dioxide in your blood stream.

This is the general process for metabolizing many different compounds, including several drugs. The more polar (charged) a molecule becomes, the better the body is at getting rid of it through the kidneys. The process of making molecules more polar is often dependent on enzymes, like ADH and ALDH. For the non-scientists reading this, if a weird-looking chemistry word ends in "-ase", it's probably an enzyme! Names of different enzymes often speak to their actual function. For instance, dehydrogenase is an enzyme that removes a hydrogen.

ADH is mostly expressed in the liver, hence the term "iron liver", which refers to someone who is able to drink a lot. Interestingly, the liver is one of the main organs that can be negatively affected by the overconsumption of alcohol which can lead to alcoholic fatty liver disease and alcoholic hepatitis, eventually progressing to cirrhosis.

Not everyone's ADH and ALDH look the same, and there are a number of genetic variations that can either increase or decrease your ability to safely metabolize alcohol. Again, ADH and ALDH are enzymes, but they are encoded for by a variety of genes including ADH1B and ALDH2. Genetic variations in these genes can actually increase or decrease your risk of developing alcoholism! But how? It all comes down to kinetics and sensitivity.

Let's start with ADH, where there are two single-nucleotide polymorphisms (SNPs) of interest in ADH1B including ADH1B*2 and ADH1B*3. Each of these variant alleles can cause a 70- to 80-fold higher turnover rate of ethanol to acetaldehyde due to a rapid release of the co-enzyme NAD+. This actually causes a protective affect against alcoholism since this genotype increases your sensitivity to alcohol. Confused? It's actually acetaldehyde (not ethanol) that is chiefly responsible for causing you to feel drunk. So, the faster you turn ethanol into acetaldehyde, the more any given alcoholic beverage will affect you.

As I said earlier, ALDH is what you rely on to get rid of acetaldehyde, and here we have one major variant allele of concern, ALDH2*2. This variant decreases the rate of converting acetaldehyde into acetate, thus increasing your sensitivity to alcohol and decreasing your risk of alcoholism. Remember, it's all about how much acetaldehyde your body has to deal with!

Some races will carry these alleles (ADH1B*2, ADH1B*3, ALDH2*2) at much higher frequencies than others, especially Asians and those of Chinese ancestry. This partially explains why Asians have a very low risk of developing alcohol use disorder compared to Caucasians, Hispanics, and Blacks in which these genetic variations are very rare. There is a tradeoff however, as many Asians will suffer from facial flushing, headache, hypotension, palpitations, tachycardia, nausea, and vomiting with alcohol use due to a buildup of acetaldehyde.

It's been hypothesized that mutations in genes such as GABRB1 can increase your risk of alcoholism, and it does seem like AUD has a genetic/hereditary component. However, the evidence behind specific genes causing AUD is sparse. What we know for sure is that certain environmental factors can drastically increase your risk, such as:

• Poverty
• Parental neglect
• Physical or sexual abuse
• Witnessing violence
• Availability of alcohol
• Peer pressure

So rather than focusing on genetics, which we can't do much about anyways, let's focus on preventing these environmental factors as much as possible!

With that being said, I hope you have a few good friends to drink with whenever you're gathering together or celebrating something special. In addition to having a good time, now you'll know exactly what's going on in your liver... Cheers, and drink responsibly.