A 6-month-old exclusively breastfed infant presents with pallor, a smooth red tongue, and hypersegmented neutrophils on peripheral smear. Serum B12 is normal, but red cell folate is low. The mother has been on methotrexate for rheumatoid arthritis. Methotrexate causes megaloblastic anemia by which mechanism?
- A Blocking intrinsic factor secretion in the stomach, preventing B12 absorption
- B Competitively blocking folate intestinal absorption by occupying folate receptors
- C Inhibiting dihydrofolate reductase (DHFR), depleting tetrahydrofolate needed for thymidylate synthesis ✓
- D Inhibiting serine hydroxymethyltransferase, blocking one-carbon transfer
Correct answer: C. Inhibiting dihydrofolate reductase (DHFR), depleting tetrahydrofolate needed for thymidylate synthesis
Explanation
Methotrexate is a structural analogue of folic acid that competitively and tightly inhibits DHFR (dihydrofolate reductase). DHFR reduces dihydrofolate (DHF) to tetrahydrofolate (THF). Without sufficient THF, the one-carbon carrier pool is depleted; specifically, 5,10-methyleneTHF cannot be regenerated for thymidylate synthase, impairing dTMP synthesis. Deficient DNA synthesis causes megaloblastic changes in rapidly dividing cells. The infant is affected via breast milk methotrexate transfer.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.