Monday, May 26, 2014

Why is Alcohol Toxic? - Part I: Cellular Damage

Every drinker has at some point had more than it was wise to have and suffered for it. Most of the time, that leads to a hangover that is unpleasant, but passes. But either consistent heavy drinking or indulging to the point of alcohol poisoning can have far more serious consequences.

While there appear to be benefits to moderate drinking, ethanol is at its root a toxin. This is due to three factors. First, its basic chemical properties, second, the ways in which it is metabolized, and third, the effects that it has on the brain.

Let's look at its chemistry first. Ethanol is similar to water in that it has a hydrogen bound to an oxygen. This allows it to interact with many hydrophilic compounds (those that dissolve well in water), because the hydrogen-oxygen bond is polarized in a similar fashion. However, instead of a second hydrogen, ethanol has a short hydrocarbon chain. This makes it more like a volatile solvent, e.g. gasoline, and allows it to interact with hydrophobic compounds as well. Having both of these features means that it can act a bit like a detergent. Detergents, like soap, also have both polar and non-polar features, which allow them to solubilize greasy molecules in water. While ethanol is not a strong detergent, at high concentrations it does have the ability to disrupt the structures of macromolecules like proteins and lipids in the cell - this is part of why ethanol is a good disinfectant.

Thankfully, for most of us, our bodies are equipped to handle limited amounts of alcohol. Even if you have never touched a drop, there will be trace amounts of ethanol in your blood from the metabolism of various compounds we consume, like ethyl esters. To keep it from accumulating to levels where it would significantly disrupt normal biological processes, most humans possess an enzyme called alcohol dehydrogenase (ADH). This enzyme catalyzes the first step in the conversion of ethanol to acetic acid, which is then fed into the citric acid cycle, where it produces energy for the cell. All well and good, on the surface.

There are a number of wrinkles in this process. First, the method by which energy is extracted from the oxidation of ethanol, is primarily by the transfer of electrons to nicotinamide adenine dinucleotide (NADH), the main carrier of reducing equivalents in the cell. This changes the redox balance in the cell, which has both direct and indirect effects. Indirectly, this can decrease the oxidation of fatty acids, as they go through a very similar oxidation process, so high levels of NADH will suppress utilization of fat. Additionally, the acetic acid formed as an end product of ethanol oxidation can be converted into acetyl-CoA, which is the starting material for fatty acid synthesis. The dual push of decreased fat burning and increased fat synthesis are two of the main drivers of alcoholic steatosis, also known as fatty liver. Taken to an extreme, this can lead to cirrhosis and liver failure.

From Wikipedia
Second, during the conversion process of ethanol to acetic acid, there is an intermediate product called acetaldehyde. This is the source of much of ethanol's toxicity and carcinogenicity. Aldehydes are very reactive, especially with amines such as those found in the amino acids that make up proteins or the nucleic acids that form DNA. The reaction between acetaldehyde and amines, especially in the reducing environment (which, remember, is enhanced by the metabolism of alcohol) found inside cells, will form adducts, disrupting the structure and functions of proteins and nucleic acids. In the case of nucleic acids, these adducts can lead to mutations that may increase the risk of cancer. Alcohol consumption is a well-known risk factor for cancer, especially esophageal cancer, which is directly related to the exposure to acetaldehyde. In small quantities, cells can remove damaged proteins and repair DNA adducts, but if errors build up they can lead to mutations or cell death.

This is particularly dangerous for people who have variations in either ADH or acetaldehyde dehydrogenase (ADLH), which catalyzes the second half of alcohol metabolism. These variations are more broadly known as 'alcohol flush syndrome', which is prevalent in people of Asian ancestry. This is caused either by a variation in ADH that results in extremely rapid conversion of ethanol to acetaldehyde, potentially coupled with a less active version of ADLH. In either case, acetaldehyde builds up to dangerous levels very quickly and the conversion to acetic acid happens slowly or not at all. The high acetaldehyde levels, in the short term, produce the characteristic flush, but in the long term produce significantly higher risks for cancer, especially of the esophagus.

Similarly, the reason why other alcohols like methanol, rubbing alcohol (isopropanol), and anti-freeze (ethylene glycol) are even more toxic is that they are oxidized to the aldehyde or ketone stage, but cannot be oxidized further to acids. This is also why the treatment for methanol or anti-freeze poisoning is to drink ethanol - ethanol binds more effectively to ADH, which fully engages the enzyme in ethanol oxidation and gives the body time to flush out the other alcohols.

Even worse compounds are produced after alcohol tolerance has built up. This is because ADH and ADLH levels remain the same, even after high chronic levels of alcohol consumption, which necessitates the liver inducing new pathways (essentially calling in for backup) for detoxification. These pathways are primarily enzymes called cytochrome P450s (CYPs). There are a whole host of these enzymes, which perform many different types of oxidations on different kinds of compounds. The common thread is that they are all designed to metabolize foreign substances into compounds that can more easily be eliminated from the body.

The primary CYP induced by alcohol consumption is called CYP2E1. While the mechanism of alcohol oxidation used by ADH is comparatively benign, that of CYP2E1 is not, as it is both less specific and more powerful. CYP2E1 directly oxidizes alcohol via the activation of molecular oxygen. A byproduct of CYP2E1 oxidation is superoxide, which is a powerful oxidizer in its own right. That can be partially ameliorated by the enzyme superoxide dismutase, but the product of that reaction is hydrogen peroxide. Anyone who has poured a bit of hydrogen peroxide on their skin to disinfect a wound knows its effects and it does not take much imagination to figure out that it's not a good thing for your cells to be producing, especially in large quantities. All of these oxidizing byproducts can go on to damage cellular components such as proteins (including CYP2E1 itself) and lipids. Lipid peroxidation has been implicated in cell wall breakdown and DNA adduct formation, which increases the risk of cancer-causing mutations.

CYP2E1 oxidation cycle via NIAAA
Adding to the danger is the fact that CYP2E1 is also implicated in the oxidation of many other drugs. The most important of these is acetaminophen, the active ingredient in Tylenol. Normally the liver deals with acetaminophen by conjugating it with an acidic sugar, glucaronic acid, which targets it for excretion in the urine. However, when concentrations are high, the glucaronidating enzymes will become saturated, which increases the concentration of free drug. CYP2E1 can oxidize acetaminophen to a compound called n-acetyl para-benzoquinone imine (NAPQI). Much like acetaldehyde, NAPQI can react with many other cellular components, especially proteins and nucleic acids, leading to protein inactivation and DNA mutations. Normally NAPQI is mopped up by conjugating with a cellular compound called glutathione, producing a harmless byproduct. However, glutathione also reacts with acetaldehyde. So high alcohol consumption will reduce the levels of free glutathione, leaving less available for detoxifying other drugs. This is why giving acetaminophen to alcoholics, especially those in the very early stages of recovery, can potentially be fatal. CYP2E1 is induced by chronic alcohol use, thus increasing the production of NAPQI. Glutathione levels will be low, which decreases the ability to detoxify NAPQI. Put together, these significantly increase the toxicity of acetaminophen. While acetaminophen is the most well-studying case of alcohol-induced CYP2E1 toxicity, a large number of other compounds that are either broken down or activated to toxic byproducts are also metabolized by CYP2E1 and will have their metabolism changed by either acute or chronic alcohol use.

This covers most of the ways in which alcohol is directly toxic to your body, primarily your liver. In the next half, I'll cover alcohol's effects on the brain and another way in which chronic alcohol consumption can be particularly dangerous.


  1. Great article! An interesting follow-up would be to analyze the beneficial effects of N-Acetyl Cysteine (NAC), lecithin, silymarin, etc. on liver health (especially NAC's ability to deal with acetaldehydes).

  2. I've taken NAC when drinking on several occasions, and every time I've had an unbearable hangover afterwards. Blocking oxidation does not appear to help me.

  3. Did part 2 get taken down or never released?

    1. Just haven't gotten around to writing it yet. Blogging has been slow lately.