Methotrexate (MTX) inhibits dihydrofolate reductase (DHFR), depleting tetrahydrofolate (THF) and blocking de novo purine and thymidylate synthesis. Leucovorin rescue after high-dose MTX works because leucovorin is:
- A 5-methyl-THF that competes with MTX for the folate binding site
- B Dihydrofolate that is converted by an alternative reductase enzyme to THF
- C 5-formyl-THF (folinic acid) that enters the folate pool downstream of DHFR, bypassing the MTX block ✓
- D Reduced form of pteridine that regenerates DHFR by displacing MTX
Explanation
Leucovorin is 5-formyl-THF (folinic acid), a reduced, formylated folate that can enter the folate metabolic pool without requiring DHFR-catalysed reduction. It is directly converted to other active THF forms (5,10-methenyl-THF, 5,10-methylene-THF) by metabolic interconversions, replenishing the depleted THF pool and rescuing purine and thymidylate synthesis. Since it bypasses DHFR, leucovorin rescue works even when DHFR is fully inhibited by MTX. Timing is critical: leucovorin must be given 24–42 hours after high-dose MTX to allow cytotoxic exposure to tumour while preventing fatal toxicity to normal cells (especially bone marrow and GI mucosa).
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.