Alcohol Metabolism & Bioavailability
Booze – most of us have had it, for better or for worse, and although we consume it, it ends up metabolized by our body. How does this metabolism occur, however? In this article, we will come to understand the finest details of what alcohol is, where it is metabolized, and how it is metabolized.
What is alcohol?
Chemically, alcohol is simply an organic chemical with a hydroxyl group (-OH) attached, somewhere, to it. There are several types of alcohol, but the one we are concerned with is ethanol [1][2].
Digestion & Absorption
Stomach
Assuming a situation in which we consume alcohol, the first place it rests is, like many other things, in the stomach [2][3]. There, the beginning of metabolism takes place referred to as “first pass metabolism” (or gastric metabolism) by various isoforms of the main enzyme alcohol dehydrogenase (ADH). First pass metabolism likely has an impact on the level of intoxication as a person with a highly active first pass metabolism will be less intoxicated than a person with a low first pass metabolism. This relationship is, however, dependent on the time of gastric emptying as a quick gastric emptying from, say, a fasted state, leads to a quick dumping of alcohol into the small intestine – this, in turn, reduces the time for ADH to be active on ethanol [3][8]. About 20% of alcohol is absorbed here [6][7].
What impacts first pass metabolism?
As previously stated, there is an inverse relationship between first pass metabolism and alcohol intoxication, but what causes this shift from fast first pass metabolism to slow, leading to greater intoxication?
Well, one reason is drug use as certain drugs (aspirin, for example) may inhibit the ability for alcohol dehydrogenase to metabolize ethanol [3][8][9]. It is also thought that alcoholics have an inhibited first pass metabolism, as well as women – possibly due to a lowered ADH concentration [3]. Granted, as with many things, genetics may play a role in determining how sensitive a person is to alcohol as the quantity of ADH may be higher or lower, inherently, between individuals [4]. Finally, it is certainly known that the speed by which gastric emptying occurs has a dramatic impact on the effectiveness of gastric metabolism, as well [3].
Intestinal tract
As with all other physiologically active molecules, alcohol passes through the epithelial walls of the intestine and is deposited into the blood stream via passive and facilitated diffusion moving from high to low concentration (high being in the intestine and low being, proportionally speaking, in the blood stream) [3][5]. About 80% of alcohol is absorbed here [6][7].
What impacts absorption?
There are a number of factors that impact absorption.
Weight
The higher a person’s weight, the lower blood alcohol concentration they have, because they have a higher body mass, more fluid, more surface area, and more blood to dilute the presence of a similar amount of alcohol consumed by someone with a smaller body weight [8].
Fasting
If a person eats, they slow the gastric emptying of the body and therefor slow the absorption [8].
Gastrointestinal Disease
Not only does alcohol, especially in large quantities, further damage the lining of the stomach, the health of the gastrointestinal system can impact general absorption, including alcohol [3][10].
Speed of Ingestion
How quickly or how slowly one consumes alcohol has an impact on absorption as the rate of ingestion, if higher, will lead to an increase in absorption until absorption becomes maximal [8].
Physiological
Concentration. If the concentration of alcohol in the stomach is high, then passive diffusion will, theoretically, increase toward the blood stream [3]. In a similar thought process, if the blood flow to the area is higher, then absorption will be increased as more blood, means more dilution, as well as greater movement through the circulatory system [3].
Where is alcohol metabolized?
Well, we know some metabolism occurs in the stomach, but the majority (~ 80-90%) of metabolism occurs in the liver with the rest of metabolism occurring in the gastrointestinal tract, brain, and pancreas [4][11].
How is alcohol metabolized?
Finishing our journey, real quick, of alcohol absorption; it moves from the blood stream and finds itself absorbed by the hepatic cells of the liver. 90% of alcohol is taken in by the liver cells and broken down systematically in the cytosol through several pathways, described below.
Ethanol diffuses across the cell membrane easily, due to its small chemical structure and its solubility in water and lipid environments [5][12]. So, once it enters the cell, there is a three step mechanism that ensues in the cytosol.
Step 1: Ethanol -> Acetaldehyde
The primary pathway is seen when ethanol is bound by an enzyme by the name of alcohol dehydrogenase (ADH), which reduces nicotinamide adenine dinucleotide (NAD+) to NADH by taking a hydrogen from the CH3CH2OH structure of ethanol [12][13]. ADH is most efficient when zinc atoms attach as these atoms further encourage a more powerful binding site with ethanol for NAD+ to be reduced by the proton (hydrogen) [14][15]. Also, water plays a significant role in the process by either attracting the ethanol molecule, attracting the NAD+ molecule, changing the conformation of the enzyme, or some other mechanism that has not been confirmed; however, water is a part of this attachment, although in what exact way is unknown [16][17]. Interestingly, the addition of water per redox reaction may be a driving reason for dehydration resulting from the consumption of alcohol and the subsequent hangover [18]. The end result is then the molecule acetaldehyde [4][12][13][19].
However, while the above pathway is the primary pathway, there are still two others. The most consequential, aside from the alcohol dehydrogenase pathway, is the microsomal ethanol-oxidizing system (MEOS) found through the vesicles in the smooth endoplasmic reticulum [13][27]. This pathway has many interactions related to lipid, carbohydrate oxidation, but we will focus our attention on ethanol [24]. This pathway becomes more and more active in face of chronic and high alcohol intake, with it being more active than the primary pathway in times of extreme alcohol intake [13][24][25][26]. MEOS is only active in this first step, and its continued reliance to move ethanol to acetaldehyde leads to a series of morphological changes within the cell and throughout the system [24].
First, as MEOS activity is needed, its chief enzyme, cytochrome P450, increases in activity, as well; however, this enzyme and class of enzymes (cytochrome) are also heavily involved in metabolizing drugs which might be a reason why heavy drinkers see a reduction in sensitivity to drug use – however, increased activity of this particular enzyme may lead to increased toxicity through, not only the synthesis of acetaldehyde, but carcinogens through free radical production and other toxic metabolites [24][25][26]. Speaking on this last point, the increase in these free radicals and harmful metabolites damage the mitochondria and harm hepatocytes to a point that we see liver damage [24]. Further, the greater use of this pathway leads to a degradation in retinol and may lead to a deficiency in vitamin A [24][25].
Secondly, as MEOS activity increases, we also see growth of the smooth endoplasmic reticulum – possibly as a precursor to greater enzyme activity [24][25][26].
Now, in terms of its actual mechanism, ethanol is oxidized via MEOS, NADPH-cytochrome P450 oxidoreductase, giving up 2 hydrogens and a dioxygen (O2) is reduced to create water [13]. However, there must also be a nicotinamide adenine dinucleotide phosphate (NADPH) present which is also used and oxidized losing a hydrogen to become NADP+. Interestingly, it is thought that this mechanism uses adenosine tri-phosphate (ATP) energy and this leads alcoholics to have a higher resting energy expenditure due to this added energy expenditure; however, I have yet to see consistent, accurate proof this is true beyond one source – maybe in the use of NADPH instead of NADH through the NAD kinase reaction, but nothing directly linked to the NADPH-cytochrome P450 oxidoreductase mechanism [28][29]. From here, acetaldehyde goes through step 2 outlined below.
Finally, the third mechanism is the least consequential in humans, yet still exists and is called the catalase pathway [13]. This mechanism is not, however, discriminant to ethanol metabolism, but rather involved in many reactions, the most known being the oxidation of fatty acids [30]. This reaction takes place in the lysosome-like organelles called peroxisomes [30]. Here, in the absence of ethanol, but high concentrations of hydrogen peroxide (H2O2), catalase neutralizes these harmful reactive oxygen species (H2O2, in this case) by attaching haem iron to hydrogen peroxide and eventually ridding it via water and oxygen [33]. However, if ethanol is present, catalase oxidizes ethanol taking 2 hydrogens, and reduces a hydrogen peroxide molecule into two water molecules and acetaldehyde [13][31].
Step 2: Acetaldehyde -> Acetate
Now, once acetaldehyde is synthesized, it moves into the mitochondria from the cytosol; although, a small amount could remain in the cytosol as the next active enzyme is also present in small amounts in the cytosol, although a majority is in the mitochondria [12]. So, assuming acetaldehyde enters the mitochondria, the enzyme aldehyde dehydrogenase (ALDH) takes over the reaction [4][12][13][19]. Interestingly, acetaldehyde is highly toxic and causes damage to tissue, so as acetaldehyde is metabolized in several areas (remember – liver, brain, pancreas, etc.), it cannot exist in the system for long durations of time [4]. It is possible that one of the ways alcohol creates a “drunk” feeling may be due to the damage and impairment of the tissue when it is synthesized in the brain, and further reaching, may be a significant contributor to, if metabolized in the liver, liver damage fatty liver syndrome, and some contribution to cancer in heavy drinkers [4].
So, the enzyme acetaldehyde dehydrogenase reduces acetaldehyde further into acetate via the use of another nicotinamide adenine dinucleotide (NAD+) [13][20]. The reaction does not occur without NAD+ and also does not occur if NAD+ is present, but acetaldehyde is not [20].
Step 3: Acetate -> Carbon Dioxide + Water
Now, we have a molecule of acetate, which is harmless and actually extremely necessary for life. Acetate, still in the mitochondria, is then used in the citric acid cycle via the synthesis of Acetyl CoA by Acetyl Coenzyme A Synthetase enzyme [21][22][23]. Without going into too much detail, this means acetate is indirectly responsible for energy production and is the likely reason why we see calories from alcohol by its integral function in the cycle. While the step posted here indicates acetate simply breaks down to carbon dioxide (CO2) and water, this is not truly the case as it allows the citric acid cycle to run through producing more byproducts than the two, but carbon dioxide and water are then excreted via the pulmonary and urinary systems, rendering alcohol’s journey to a close [4].
How quickly is it metabolized?
The speed by which we are able to metabolize alcohol is variable and dependent on the delivery to the metabolic sites, the existing levels of drugs and alcohol, the regularity of alcohol consumption, the presence of needed molecules (NAD, NADP, zinc, etc.), among many other contingencies. For example, one key difference is the dramatic difference in the quantity of the chief enzyme alcohol dehydrogenase between men and women, as women tend to have far less (somewhere between 40-80% less) in their liver and stomach [34].
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