Alcohol metabolism

Pathways

Ethanol is metabolised predominantly in the liver via alcohol dehydrogenase (ADH) to acetaldehyde, then aldehyde dehydrogenase (ALDH) to acetate - a two-step pathway whose genetic variation and saturation kinetics explain much of the individual variability in alcohol tolerance and toxicity

Genetic polymorphisms in ADH and ALDH vary significantly by population - a common ALDH2 variant (particularly prevalent in East Asian populations) produces markedly reduced enzyme activity, causing the "alcohol flush reaction" and altered drinking patterns/risk profile in affected individuals

ADH oxidises ethanol to acetaldehyde (itself toxic/carcinogenic); ALDH rapidly oxidises acetaldehyde to acetate (relatively harmless, further metabolised to CO2/water) - the *ALDH22 variant** produces a markedly less active enzyme, causing acetaldehyde accumulation and the flushing/nausea/tachycardia reaction after even modest alcohol intake (the biological basis of disulfiram's mechanism - disulfiram blocks ALDH, deliberately reproducing this reaction to reinforce abstinence)
CYP2E1 (an inducible microsomal pathway) provides a secondary metabolic route, becoming proportionally more important with chronic heavy use as it is induced - and importantly generates reactive oxygen species as a byproduct, contributing to alcohol-related oxidative liver injury
Alcohol metabolism follows zero-order kinetics at typical drinking levels (a roughly constant amount metabolised per hour regardless of blood concentration, since the enzyme system is saturated) - unlike most drugs, which follow first-order kinetics

Blood alcohol concentration trajectory can be estimated using the zero-order elimination rate (~10-15mg/dL/hour on average, though with individual variation), relevant to forensic and clinical timing estimates

Disulfiram exploits ALDH inhibition therapeutically (deliberately inducing the aversive acetaldehyde reaction to reinforce abstinence) - patients must be counselled explicitly about the severity of the reaction and strict alcohol avoidance including hidden sources (some medications, mouthwash)
Chronic heavy alcohol use induces CYP2E1, which also metabolises paracetamol to a toxic intermediate (NAPQI) - explaining why chronic heavy drinkers are at increased risk of paracetamol hepatotoxicity even at standard/modestly supratherapeutic doses

Alcohol-related liver disease, disulfiram mechanism, paracetamol hepatotoxicity (increased risk with chronic alcohol use via CYP2E1 induction), the ALDH2 flush reaction

Acetaldehyde (not ethanol itself) is directly responsible for much of alcohol's acute toxicity and is a recognised carcinogen - genetic variation in its clearance (ALDH2 polymorphisms) has real clinical and population-level implications for alcohol-related disease risk, not just symptom tolerance

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