A 64-year-old woman with newly diagnosed colorectal cancer receives standard-dose fluorouracil and within days develops severe mucositis, diarrhea, neutropenia, and neurotoxicity far beyond expected toxicity. Genotyping shows homozygous loss-of-function variants in DPYD. Which enzyme activity is absent, and what does it normally do?
- A Thymidylate synthase, which methylates dUMP to dTMP
- B Dihydropyrimidine dehydrogenase, which reduces fluorouracil to dihydrofluorouracil in the first catabolic step ✓
- C Orotate phosphoribosyltransferase, which converts orotate to OMP
- D Thymidine phosphorylase, which cleaves thymidine to thymine
Correct answer: B. Dihydropyrimidine dehydrogenase, which reduces fluorouracil to dihydrofluorouracil in the first catabolic step
Explanation
More than 80 percent of administered fluorouracil is degraded by dihydropyrimidine dehydrogenase, the rate-limiting first enzyme of pyrimidine catabolism. DPYD loss-of-function abolishes this clearance, causing profound drug exposure and life-threatening toxicity. Testing for DPYD variants before fluorouracil dosing is now standard practice.
Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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