Sources and Body Distribution
Ethanol is constantly present in the human internal environment. Endogenous alcohol (at concentrations of 0.0004–0.001 g/L) is a natural metabolite. It is formed during the cellular conversion of glucose via the pyruvate pathway, as well as through fermentation processes carried out by normal microflora in the gut and respiratory tract. Exogenous ethanol enters the body from the outside via alcoholic beverages and certain foods (e.g., kefir, juices, bread).
Absorption of exogenous alcohol is rapid. It begins already in the oral mucosa. The stomach absorbs 20–30% of the ingested volume, and the small intestine absorbs the remaining 70–80%. The substance reaches peak blood concentrations within 30–60 minutes after consumption. Being an amphiphilic compound, ethanol easily crosses biological barriers (including the blood-brain barrier), disrupting the structure and function of brain cell membranes. Only about 10% of the substance leaves the body unchanged via the kidneys, lungs, and sweat glands. The remaining bulk is sent to the liver for processing.
Primary Ethanol Oxidation Pathway
When small and moderate doses of alcohol are consumed, oxidation via NAD-dependent enzyme systems dominates in the liver. The biochemical process occurs in two steps:
- Oxidation to acetaldehyde. The enzyme alcohol dehydrogenase acts as the catalyst. The coenzyme $NAD^+$ accepts hydrogen from the alcohol molecule, becoming reduced to $NADH$. This yields the intermediate product, acetaldehyde.
- Oxidation to acetic acid. The enzyme aldehyde dehydrogenase enters the action. Utilizing a water molecule, it oxidizes toxic acetaldehyde into acetic acid, reducing a fresh batch of $NAD^+$ to $NADH$.
The ultimate fate of acetic acid depends on the metabolic status. It is converted into Acetyl-CoA. Normally, this substrate enters the citrate cycle (Krebs cycle), where it is oxidized to carbon dioxide and water with energy release. However, in the presence of excess alcohol, the capacity of the cycle is exceeded. Excess Acetyl-CoA is shunted toward the synthesis of fatty acids, cholesterol, and hepatic fat accumulation.
Microsomal Ethanol-Oxidizing System (MEOS)
When large volumes of ethanol enter the body, the classical pathway becomes overloaded. The liver then activates a backup mechanism: the microsomal ethanol-oxidizing system. The key active component here is the cytochrome P450 2E1 ($CYP2E1$) isoenzyme. This system oxidizes alcohol to acetaldehyde using molecular oxygen and the coenzyme $NADPH$.
Features of MEOS function:
- It is activated (induced) only in response to high doses of ethanol.
- It generates reactive oxygen species (ROS), which trigger lipid peroxidation (LPO) and damage cell membranes.
- Cytochrome P450 lacks strict substrate specificity. It simultaneously participates in the biotransformation of numerous drugs. In individuals with alcohol use disorder, the activity of this enzyme is elevated. Clinically, this means that many medications are degraded in the liver too rapidly, causing their therapeutic efficacy to drop sharply.
Biochemical Mechanisms of Toxicity
Toxic consequences are driven by the accumulation of aggressive metabolic byproducts:
- Acetaldehyde. This aldehyde is considerably more toxic than the parent alcohol. It forms stable bonds with amino and thiol groups of proteins and enzymes. This not only provokes severe hangover symptoms but also increases the risk of cancers of the oral cavity, pharynx, and urinary tract. Furthermore, acetaldehyde inhibits NADH dehydrogenase and impairs hemoglobin's oxygen-carrying capacity (reducing ATP synthesis). In chronic alcohol consumption, acetaldehyde reacts with serotonin and dopamine to form specific 'alcoholic opioids' that bind to opiate receptors, inducing euphoria and dependence (one of which is even excreted in the urine and serves as a marker of alcoholism).
- Excess $NADH$. Massive coenzyme reduction leads to an overabundance of $NADH$. This shifts metabolic equilibria: lactate synthesis is activated (lactic acidosis), gluconeogenesis is blocked (leading to hypoglycemia), and the Krebs cycle is inhibited.
- ROS and excess acetate. These compound the picture by causing oxidative stress and predisposing to acidosis.