Normal lactate oxidation
Lactate produced in tissues can be used as an energy substrate or a precursor for glucose synthesis.
In the liver, part of the pyruvate formed from lactate is oxidized to carbon dioxide and water. This process yields energy in the form of ATP molecules, which is consumed in gluconeogenesis.
Lactate is also actively utilized by other tissues, primarily the kidneys and myocardium, where it is likewise oxidized to $CO_2$ and $H_2O$ with the generation of ATP.
At rest in skeletal muscles, the $NAD^+/NADH$ ratio increases. As a result, lactate is able to convert back into pyruvate, which is then fully oxidized.
Lactic acidosis
If lactate is not utilized for glucose synthesis (e.g., due to gluconeogenesis enzyme defects), lactic acid accumulates in the blood. This causes a drop in pH and the development of lactic acidosis.
Physiological (short-term) lactic acidosis occurs in healthy individuals during intense muscular work. The body compensates for this condition through pulmonary hyperventilation, accelerating the removal of carbon dioxide. The primary role here is played by the buffer reaction converting hydrogen ions and bicarbonate into carbonic acid, and then into $CO_2$ and water.
In uncompensated lactic acidosis, blood lactate levels exceed 5 mmol/L (the norm is up to 2 mmol/L), and blood pH drops below 7.25.
Causes of pathological lactate elevation include:
- Tissue hypoxia, which activates anaerobic oxidation.
- Liver damage (cirrhosis, toxic dystrophies), reducing lactate utilization.
- Hereditary defects (glucose-6-phosphatase deficiency, pyruvate dehydrogenase complex defects).
- Hypovitaminoses $B_1$, $B_2$, $PP$, disrupting coenzyme functions.
Ethanol metabolism
About 90% of all ethanol is metabolized in the liver. The main enzyme of this process is alcohol dehydrogenase, the lion's share of which (95%) is localized in hepatocytes (the rest is in the brain, kidneys, lungs, and intestines).
Alcohol catabolism involves two dehydrogenation reactions. This results in the formation of acetyl-CoA, which is oxidized in the citric acid cycle. Part of the ethanol is oxidized with the participation of microsomal enzymes. Alcohol oxidation requires a colossal amount of coenzymes: 125 g of ethanol consumes the same amount of $NAD^+$ as 500 g of carbohydrates.
Effect of ethanol on carbohydrate metabolism
Ethanol catabolism leads to a sharp increase in the concentration of NADH.
This excess of reducing equivalents shifts the equilibrium of the reaction catalyzed by lactate dehydrogenase (LDH) toward lactate formation. As a result, the concentration of pyruvate decreases, leading to the slowdown and suppression of gluconeogenesis.
In acute alcohol poisoning in an unconscious patient, laboratory tests reveal hypoglycemia (glucose drop to 50 mg/dL) and hyperlactatemia (lactate rise to 2 mmol/L with a norm of 1 mmol/L), while the blood alcohol level significantly exceeds normal values. The excessively high $NADH/NAD^+$ ratio shifts the pyruvate-to-lactate conversion reaction, and the deficiency of pyruvate and oxaloacetate inhibits glucose synthesis, causing severe hypoglycemia.
Briefly: answers to topical questions
Which specific enzymes catalyze the conversion of ethanol to acetyl-CoA?
The conversion of ethanol to acetyl-CoA proceeds in three successive stages and is catalyzed by specific enzymes.
- Alcohol dehydrogenase — oxidizes ethanol to acetaldehyde (coenzyme NAD⁺).
- Acetaldehyde dehydrogenase — catalyzes the oxidation of acetaldehyde to acetate (coenzyme NAD⁺).
- Acetyl-CoA synthetase — converts acetate into acetyl-CoA with the participation of coenzyme A and the expenditure of ATP energy.
What ethanol oxidation systems exist in hepatocytes besides alcohol dehydrogenase?
In addition to the alcohol dehydrogenase system, two other parallel metabolic systems for ethanol oxidation function in the liver.
- Microsomal ethanol oxidizing system (MEOS) — an inducible pathway whose main enzyme is cytochrome P450 II E1 (CYP2E1). This system is activated upon consumption of large amounts of ethanol and becomes predominant during chronic alcoholism.
- Peroxisomal catalase system — functions as an auxiliary metabolic pathway.
Class and exam questions
Why is gluconeogenesis inhibited during ethanol metabolism?
Ethanol oxidation leads to an excess of NADH. This shifts the lactate dehydrogenase reaction toward lactate formation, lowering the level of pyruvate required for gluconeogenesis.
How does the body compensate for physiological lactic acidosis?
Through pulmonary hyperventilation. Via a buffer reaction, hydrogen binds with bicarbonate to form carbonic acid, which breaks down into water and carbon dioxide, rapidly eliminated through respiration.
Where is ethanol mainly oxidized in the body?
The bulk of ethanol (about 90%) is oxidized in the liver using the enzyme alcohol dehydrogenase.
What else to study on this topic
- Gluconeogenesis from glycerol during starvation
- Diagram of glycerol conversion to glucose and energy costs
- Gluconeogenesis from amino acids (glutamate)
- Oxidative deamination of glutamate
- Energy balance of glutamate conversion to glucose
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