Pathophysiology
II-5. The metabolism of alcohol
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Ethanol Metabolism
- Metabolized in the liver (~10 g/hour); acetaldehyde always produced (responsible for all consequences — headache, nausea). ALDH → acetaldehyde to acetate. Large NADH production drives complications.
Three Pathways
- ADH (cytosol): uses NAD⁺ → NADH; ethanol → acetaldehyde. Main pathway in occasional drinkers.
- CYP2E1 (ER): most important in chronic alcoholism; rapid activity → incomplete O₂ reduction → ROS/H₂O₂ → oxidative stress.
- Catalase (peroxisome).
Variations (Polymorphism)
- ALDH polymorphism (Asian): slow acetaldehyde → acetate → flushing, sweating, vomiting (“Asian flush”). Disulfiram inhibits ALDH → deterrent in chronic alcoholism.
- ADH polymorphism (Asian): overactive → acetaldehyde accumulation → feel sicker.
CYP2E1
- More pronounced in chronic alcoholics (broken down slower).
- Casual drinkers: enzyme degraded in hours (phosphorylation → ubiquitination → proteasome, T½ hours).
- Chronic (induced): ethanol binds enzyme → conformational change → no degradation (T½ 30–40 h). Induces whole ER → accelerated biotransformation.
- Consequences: ↑O₂ use → hypoxia; incomplete O₂ reduction → H₂O₂/ROS → oxidative stress; altered drug efficacy; toxic intermediate accumulation.
Effects on Drug Metabolism
- Non-alcoholic: alcohol competes with drug for CYP2E1 → ↓drug metabolism.
- Alcoholic: high CYP2E1 → when sober, drug metabolized faster → more toxic intermediates; when drinking, metabolism normalizes (competition).
Paracetamol
- Antipyretic/analgesic (1–1.5 g/day); hepatotoxic >4 g/day (10 g → massive necrosis/acute liver failure; 15 g → lethal).
- Metabolized by CYP2E1 → hepatotoxic intermediate (NAPQI). Alcoholics: ↑CYP2E1 → normal doses dangerous; impaired GSH conjugation → even more toxic metabolite accumulation.
一問一答
▶Where and how fast is ethanol metabolized?
In the liver, at about 10 g/hour.
▶Why is acetaldehyde important in ethanol metabolism?
It is always produced and is responsible for all the consequences (headache, nausea); ALDH converts it to acetate.
▶What is the ADH pathway of ethanol metabolism and when does it dominate?
A cytosolic pathway using NAD⁺ → NADH to convert ethanol to acetaldehyde; the main pathway in occasional drinkers.
▶What is the role of CYP2E1 in alcohol metabolism?
An ER pathway most important in chronic alcoholism; its rapid activity causes incomplete O₂ reduction → ROS/H₂O₂ → oxidative stress.
▶What causes the 'Asian flush' reaction?
ALDH polymorphism with slow acetaldehyde-to-acetate conversion, leading to flushing, sweating, and vomiting.
▶How does disulfiram work as an alcohol deterrent?
It inhibits ALDH, causing acetaldehyde accumulation and unpleasant symptoms — used as a deterrent in chronic alcoholism.
▶Why does CYP2E1 persist in chronic alcoholics?
Ethanol binds the enzyme causing a conformational change that prevents degradation (T½ 30–40 h vs hours in casual drinkers), inducing the whole ER.
▶How is CYP2E1 normally degraded in casual drinkers?
Via phosphorylation → ubiquitination → proteasome, with a half-life of hours.
▶What are the consequences of CYP2E1 induction?
Increased O₂ use (hypoxia), incomplete O₂ reduction → H₂O₂/ROS (oxidative stress), altered drug efficacy, and toxic intermediate accumulation.
▶How does alcohol affect drug metabolism in non-alcoholics?
Alcohol competes with the drug for CYP2E1, reducing drug metabolism.
▶How does drug metabolism differ in a sober chronic alcoholic versus while drinking?
When sober, high CYP2E1 metabolizes drugs faster → more toxic intermediates; while drinking, competition normalizes metabolism.
▶What is the toxic metabolite of paracetamol and which enzyme produces it?
NAPQI, produced by CYP2E1.
▶Why is paracetamol especially dangerous in alcoholics?
Increased CYP2E1 makes even normal doses dangerous, and impaired GSH conjugation allows more toxic NAPQI to accumulate.
▶What are the hepatotoxic and lethal doses of paracetamol?
Therapeutic 1–1.5 g/day; hepatotoxic >4 g/day (10 g causes massive necrosis/acute liver failure; 15 g is lethal).
▶What is the third (minor) ethanol metabolism pathway?
Catalase, located in peroxisomes.
▶How does ADH polymorphism in some Asian populations affect drinking?
Overactive ADH causes acetaldehyde accumulation, making the person feel sicker.
▶Why does large NADH production from ethanol matter?
The large NADH load drives the metabolic complications of alcohol metabolism.
▶In which subcellular compartment does the ADH pathway operate?
The cytosol.
▶Why does CYP2E1 cause hypoxia in chronic alcoholics?
Its high activity increases O₂ consumption.
▶What enzyme converts acetaldehyde to acetate?
ALDH (aldehyde dehydrogenase).