Biochemistry · Metabolic pathway
Ethanol metabolism !
The liver oxidises ethanol to acetaldehyde and then to acetate; along the way it makes a lot of NADH, which upsets the rest of metabolism.
Updated 2026-11-01
Interactive map
Balance: NADH +2ATP -2
Key facts
- Ethanol → acetaldehyde (alcohol dehydrogenase, cytosol) → acetate (ALDH2, mitochondria); each step reduces one NAD⁺ to NADH.
- With heavy or chronic drinking the MEOS joins in: CYP2E1 in the endoplasmic reticulum oxidises ethanol with NADPH and O₂, and it is inducible (tolerance).
- Alcohol dehydrogenase is saturated by little alcohol: elimination follows zero-order kinetics (an almost fixed amount per hour).
- The high NADH/NAD⁺ ratio pushes pyruvate to lactate, slows gluconeogenesis and favours fat synthesis: lactic acidosis, hypoglycaemia and fatty liver.
- Acetaldehyde is the toxic one: if ALDH2 fails (ALDH2*2 variant or disulfiram) it builds up and causes flushing, nausea and tachycardia.
- Also called
- Alcohol oxidation
Regulation
- There is no hormonal control: the rate is set by the amount of alcohol dehydrogenase and by how fast mitochondria reoxidise NADH.
- Chronic drinking induces CYP2E1 (several-fold more activity): faster elimination, more free radicals and more activation of toxins such as acetaminophen.
- Genetic variants change the speed: ADH1B*2 makes acetaldehyde faster and ALDH2*2 removes it poorly; both protect against dependence.
The steps, one by one
- Step 1 · Alcohol dehydrogenase (ADH, class I) Ethanol + NAD⁺ ⇌ Acetaldehyde + NADHIn the hepatocyte cytosol it removes two hydrogens from ethanol and turns it into acetaldehyde. MEOS branch: with heavy or chronic drinking, CYP2E1 in the endoplasmic reticulum does the same oxidation using NADPH and O₂, and releases free radicals.If it fails: The same enzyme oxidises methanol to formaldehyde and ethylene glycol to glycolaldehyde: the first step towards their toxic acids. Methanol poisoning →
- Step 2 · Mitochondrial aldehyde dehydrogenase (ALDH2) irreversible Acetaldehyde + NAD⁺ + H₂O → Acetate + NADHIn the mitochondrion it oxidises toxic acetaldehyde to acetate, which leaves the liver into the blood.If it fails: If ALDH2 does not work, acetaldehyde builds up: facial flushing, nausea, headache, tachycardia and hypotension (disulfiram-like reaction). Disulfiram–ethanol reaction →
- Step 3 · Acetyl-CoA synthetase (mitochondrial ACSS1, cytosolic ACSS2) irreversible Acetate + ATP + coenzyme A → Acetyl-CoA + amp + pyrophosphateMostly in heart, muscle and brain, it activates the acetate arriving in the blood by joining it to coenzyme A; it costs the equivalent of two ATP.If it fails: No classic human disease from its deficiency is known; in a liver flooded with NADH, acetyl-CoA is diverted to fat and ketone bodies.
- Step 4 · Citrate synthase (entry to the Krebs cycle) irreversible Acetyl-CoA + oxaloacetate + H₂O → Citrate + coenzyme AIn the tissues that receive it, the acetyl-CoA from alcohol joins oxaloacetate and is burned in the Krebs cycle: this is how ethanol supplies energy (empty calories).If it fails: In the drinker's liver oxaloacetate is turned into malate by excess NADH: it is missing for this step and for gluconeogenesis. Lactic acidosis →
Clinical notes
- Hypoglycaemia in a fasting drinker or a child who swallows alcohol: excess NADH turns pyruvate into lactate and oxaloacetate into malate, and gluconeogenesis stops.
- Fatty liver: NADH slows β-oxidation and supplies glycerol-3-phosphate to build triglycerides.
- Alcoholic ketoacidosis: with fasting and vomiting β-hydroxybutyrate dominates (because of NADH), which nitroprusside dipsticks barely detect.
- Lactate competes with urate in the renal tubule: alcohol can trigger gout attacks.
- Methanol and ethylene glycol use the same enzymes to become toxic acids; blocking alcohol dehydrogenase with fomepizole (or ethanol) is the basis of the antidote.
Related conditions
- Alcoholic liver disease (biochemistry)
- Disulfiram–ethanol reaction
- Methanol poisoning
- Ethylene glycol poisoning
- Lactic acidosis
- Wernicke encephalopathy (thiamine deficiency)
- Gout
- Cirrhosis
Related
- Alcohol dehydrogenase (ADH)
- Aldehyde dehydrogenase 2 (ALDH2)
- Cytochrome P450 2E1 (CYP2E1, MEOS)
- Ethanol
- Acetaldehyde
- Fomepizole (4-methylpyrazole)
- Acetyl-CoA
- Citrate synthase
- Krebs cycle (citric acid cycle)
- Gluconeogenesis
- Ketogenesis (ketone body synthesis)
- Fatty acid synthesis (lipogenesis)
- Mitochondrial NADH shuttles
- Thiamine (vitamin B1)
Test yourself
Think of the answer, then tap the question to see it.
Why can alcohol on an empty stomach cause hypoglycaemia?
Because excess NADH turns pyruvate into lactate and oxaloacetate into malate; without those substrates gluconeogenesis stops.
Which enzyme forms the MEOS and why does it explain tolerance?
CYP2E1; chronic drinking induces it, so ethanol is cleared faster.
Which molecule causes flushing and nausea when ALDH2 fails?
Acetaldehyde, which builds up because it is not oxidised to acetate.
What kind of kinetics does ethanol elimination follow at usual concentrations?
Zero order: alcohol dehydrogenase is saturated and removes an almost fixed amount per hour.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Ethanol oxidation (Reactome, 2026); ADH1B: All-trans-retinol dehydrogenase [NAD(+)] ADH1B (human), UniProt P00325 (UniProt, 2026); ALDH2: Aldehyde dehydrogenase, mitochondrial (human), UniProt P05091 (UniProt, 2026); Alcoholic liver disease: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.