Ethanol metabolism

Sources and body distribution

Ethanol is always present in the human internal environment. Endogenous alcohol (at a concentration of 0.0004–0.001 g/L) is a natural metabolite. It is formed during the cellular conversion of glucose via the pyruvate stage, as well as through alcoholic fermentation carried out by the normal microflora of the intestines and respiratory tract. Exogenous ethanol enters the body from the outside—via alcoholic beverages and certain food products (e.g., kefir, juices, bread).

The absorption of exogenous alcohol occurs rapidly. It begins right 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 its peak blood concentration 30–60 minutes after consumption. Being an amphiphilic compound, ethanol easily crosses 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 utilization.

Main pathway of ethanol oxidation

When small and moderate doses of alcohol are consumed, oxidation via NAD-dependent enzyme systems dominates in the liver. The biochemical process proceeds in two stages:

1. Oxidation to acetaldehyde. The enzyme alcohol dehydrogenase acts as a catalyst. The coenzyme is NAD⁺, which accepts hydrogen from the alcohol molecule and converts into the NADH form. As a result, an intermediate product—acetaldehyde—is formed.
2. Oxidation to acetic acid. The enzyme aldehyde dehydrogenase comes into play. With the participation of a water molecule, it oxidizes toxic acetaldehyde to acetic acid, reducing a new portion of NAD⁺ to NADH.

The subsequent 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 burned down to carbon dioxide and water with the release of energy. However, in the presence of excess alcohol, the capacity of the cycle is insufficient. Excess Acetyl-CoA is shunted toward the synthesis of fatty acids, cholesterol, and the accumulation of fat in the liver.

Microsomal ethanol-oxidizing system (MEOS)

When large amounts of ethanol enter the body, the classical pathway becomes overloaded. The liver then activates a backup mechanism—the microsomal ethanol-oxidizing system. The main working link here is the cytochrome isoenzyme—P450 II E1. This system oxidizes alcohol to acetaldehyde using molecular oxygen and the coenzyme NADPH.

Features of MEOS functioning:

• It is activated (induced) only at high doses of ethanol.
• It generates reactive oxygen species (ROS), which trigger lipid peroxidation (LPO) and destroy membranes.
• Cytochrome P450 lacks substrate specificity. It is simultaneously responsible for the biotransformation of many drugs. In individuals with alcoholism, the activity of this enzyme is elevated. Clinically, this means that many pharmaceutical drugs are broken down in the liver too rapidly, causing their therapeutic efficacy to drop sharply.

Biochemical mechanisms of toxicity

Toxic consequences are associated with the accumulation of aggressive metabolic products:

• Acetaldehyde. This aldehyde is much more toxic than the parent alcohol. It forms strong bonds with the amino and thiol groups of proteins and enzymes. This not only triggers a severe hangover syndrome but also increases the risk of developing cancer of the oral cavity, pharynx, and urinary tract. Furthermore, acetaldehyde inhibits NADH dehydrogenase and reduces the ability of hemoglobin to carry oxygen (ATP synthesis drops). In chronic alcoholism, acetaldehyde reacts with serotonin and dopamine. Specific "alcohol opioids" are formed, which bind to opiate receptors, causing euphoria and addiction (one of them is even excreted in urine and serves as a marker of alcoholism).
• Excess NADH. Massive reduction of coenzymes leads to an overabundance of NADH. This causes an equilibrium shift: lactate synthesis is activated (lactic acidosis), gluconeogenesis is blocked (hypoglycemia occurs), and the Krebs cycle is inhibited.
• ROS and excess acetate. They complete the picture with oxidative stress and a tendency toward acidosis.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The mechanism of formation of "alcohol opioids" during the interaction of acetaldehyde with neurotransmitters.
• The effect of cytochrome P450 II E1 induction on the pharmacokinetics of medicinal drugs.
• The pathogenesis of fatty liver disease against the background of excess Acetyl-CoA and NADH.
• Chemical reactions of acetaldehyde with proteins and receptors: adduct formation and carcinogenesis.
• Oxidative stress and lipid peroxidation during MEOS activation.

Other topics in the section "Detoxification of toxic substances in the liver"

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