acetaldehyde dehydrogenase

Ethanol metabolism occurs in two main steps: first, alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde in the cytosol; second, acetaldehyde dehydrogenase (ALDH2), located in mitochondria, oxidizes acetaldehyde to acetate, which is then converted to acetyl-CoA and enters the citric acid cycle. Both reactions require NAD+ as a cofactor, generating NADH, which shifts cellular redox state and contributes to metabolic effects of alcohol (e.g., hypoglycemia, lactic acidosis, fatty liver via increased NADH/NAD+ ratio favoring lipogenesis and inhibiting gluconeogenesis).

ALDH2 deficiency, especially the ALDH2*2 allele (glu487lys mutation), is common in East Asian populations (~30-50% prevalence) and results in reduced enzymatic activity. This causes accumulation of acetaldehyde after alcohol intake, producing the 'Asian flush syndrome'—facial flushing, tachycardia, nausea, and headache—due to acetaldehyde's vasodilatory and toxic effects. This polymorphism is protective against alcohol use disorder due to the unpleasant symptoms but is associated with increased risk of esophageal cancer with chronic alcohol use, likely due to acetaldehyde's carcinogenic properties (it forms DNA adducts).

Clinically, disulfiram (Antabuse) is used as aversive thertherapy for alcohol use disorder; it irreversibly inhibits ALDH2, causing acetaldehyde accumulation upon alcohol ingestion, leading to flushing, headache, nausea, vomiting, and hypotension—mimicking the ALDH2-deficient phenotype. Metronidazole and some other drugs can cause a similar disulfiram-like reaction when combined with alcohol due to ALDH inhibition.

Understanding this pathway is high-yield for USMLE Step 1 biochemistry (enzyme kinetics, NADH/NAD+ ratio effects) and pharmacology (mechanism of disulfiram), as well as genetics (polymorphisms affecting drug/alcohol metabolism).