A 40-year-old man started on treatment for alcohol dependence attends a wedding, consumes two drinks, and develops facial flushing, throbbing headache, nausea and tachycardia within minutes. The drug he was taking acts on alcohol metabolism by which mechanism?

• A Competitive reversible inhibition of alcohol dehydrogenase
• B Competitive inhibition of acetaldehyde dehydrogenase by a stable transition-state analogue
• C Non-competitive inhibition of mitochondrial NADH dehydrogenase
• D Irreversible (suicide) inhibition of aldehyde dehydrogenase after metabolic activation by the target enzyme itself ✓

Explanation

Disulfiram is a prototype mechanism-based (suicide) inhibitor: aldehyde dehydrogenase itself oxidises it to a reactive metabolite that covalently inactivates the enzyme. Acetaldehyde from ethanol oxidation therefore accumulates, causing the flushing, headache and tachycardia used therapeutically as aversion therapy. Option A is wrong because alcohol dehydrogenase is not the target, and option B is wrong because the inactivation is covalent and irreversible, not a reversible transition-state mimic.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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