Methotrexate mode of action
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Methotrexate mechanism of action folate DHFR anti-inflammatory adenosine authoritative source
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https://pmc.ncbi.nlm.nih.gov/articles/PMC6360124/
Methotrexate (MTX) is a folate antagonist with dose-dependent actions.
1. Anticancer action: inhibits DNA synthesis
- MTX competitively binds and inhibits dihydrofolate reductase (DHFR).
- This prevents conversion of dihydrofolate to tetrahydrofolate (THF).
- THF is required for one-carbon transfer reactions in synthesis of:
- Thymidylate (dTMP)
- Purine nucleotides
- Therefore, DNA synthesis is impaired, causing S-phase arrest and death of rapidly dividing cells, such as malignant cells, bone-marrow precursors, and gastrointestinal mucosal cells.
This is the main mechanism at high doses used in cancer therapy. Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 953.
2. Low-dose anti-inflammatory/immunomodulatory action
At the low weekly doses used for rheumatoid arthritis, psoriasis, and some inflammatory disorders, its clinical benefit is mainly immunomodulatory rather than simply cytotoxic:
- MTX polyglutamate metabolites inhibit AICAR transformylase (ATIC).
- This increases intracellular AICAR, which promotes accumulation and extracellular release of adenosine.
- Adenosine acts on immune-cell receptors to reduce:
- leukocyte adhesion and migration
- neutrophil and macrophage activation
- pro-inflammatory cytokine activity
- T-cell proliferation
The resulting effect is suppression of inflammation. Evidence reviews identify adenosine signaling as the leading explanation for low-dose MTX action in rheumatoid arthritis, as described in this mechanism review.
One-line exam answer:
Methotrexate is a folic-acid analogue that inhibits DHFR, reducing tetrahydrofolate-dependent purine and thymidylate synthesis and thereby inhibiting DNA synthesis; at low doses it increases extracellular adenosine via ATIC inhibition, producing anti-inflammatory and immunosuppressive effects.
Methotrexate is a folic-acid analogue that inhibits DHFR, reducing tetrahydrofolate-dependent purine and thymidylate synthesis and thereby inhibiting DNA synthesis; at low doses it increases extracellular adenosine via ATIC inhibition, producing anti-inflammatory and immunosuppressive effects.
Recent systematic reviews retrieved were focused on toxicity or pharmacogenetics rather than a mechanism update, so they do not materially alter this explanation (PMIDs: 42403312, 42104114, 38501267).
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