A competitive enzyme inhibitor reduces the apparent affinity of an enzyme for its substrate. In clinical pharmacology, which drug mechanism is an example of reversible competitive inhibition of a metabolic enzyme?

• A Aspirin irreversibly acetylating cyclooxygenase
• B Methotrexate competitively inhibiting dihydrofolate reductase (DHFR) ✓
• C Allopurinol forming a covalent oxypurinol-xanthine oxidase complex
• D Omeprazole irreversibly binding H+/K+-ATPase

Explanation

Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), competing with the natural substrate dihydrofolate (DHF) for the enzyme active site, since methotrexate is a structural analogue of DHF. High concentrations of DHF can displace methotrexate (reversible competitive inhibition), which is the basis for leucovorin (folinic acid) rescue in high-dose methotrexate therapy. Aspirin (option A) and omeprazole (option D) are irreversible inhibitors (covalent modification). Allopurinol's active metabolite oxypurinol forms a tight but technically reversible (though very slow off-rate) complex with xanthine oxidase — it is often classified as a mechanism-based (suicide) inhibitor.

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

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