A patient with colorectal cancer develops severe mucositis, neutropenia and diarrhoea after a standard dose of fluorouracil. Genotyping reveals complete deficiency of dihydropyrimidine dehydrogenase. The reason this enzyme defect causes life-threatening 5-FU toxicity is:

• A DPD is the enzyme responsible for catabolic breakdown of more than 80 percent of administered 5-FU ✓
• B DPD activates 5-FU to its phosphorylated cytotoxic form
• C DPD transports 5-FU out of tumour cells
• D DPD repairs thymidylate synthase damaged by 5-FU

Explanation

About 85 percent of a fluorouracil dose is degraded by dihydropyrimidine dehydrogenase in the liver. Complete DPD deficiency allows full doses to enter anabolic pathways, producing excessive thymidylate synthase inhibition and catastrophic mucosal and marrow toxicity. Activation of 5-FU to FdUMP occurs intracellularly via thymidine phosphorylase and other enzymes, not DPD. Testing for DPD variants is now recommended before fluoropyrimidine dosing in many settings.

Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.