Description
Methotrexate (MTX) is similar in structure to folic acid and aminopterin . It acts by inhibiting the metabolism of folic acid and blocking key enzymes in the synthesis of purines and pyrimidines required for cell proliferation. MTX is known to induce adenosine release, which mediates many of its anti-inflammatory effects, including the reduction of proinflammatory cytokines. Formulations containing MTX have been used as immunosuppressants, in the treatment of cancer, autoimmune disease, ectopic pregnancy, and for the induction of medical abortions. MTX formulations have been considered the gold standard of disease-modifying antirheumatic drug (DMARD) therapy to treat both the immune-inflammatory and joint destructive processes of rheumatoid arthritis.
Chemical Properties
yellow to orange crystalline powder
Uses
Potent inhibitor of dihydrofolate reductase and agent for antitumor studies. Use to inhibit dihydrofolate reductase in DHFR-based protein expression systems. Also shows immunosuppressive effects in, e.g., rheumatoid arthritis.
Uses
Methotrexate hydrate has been used:
- as a dihydrofolate (DHFR)inhibitor in sphere forming assay culture
- as a component of dulbecco′ modified Eagle′s medium (DMEM) for selection of transfected cells
- in viability and co-culture assays
Definition
ChEBI: Methotrexate hydrate is a member of folic acids.
Biochem/physiol Actions
Methotrexate is an allosteric inhibititor of dihydrofolate reductase (DHFR), the enzyme that catalyzes the conversion of dihydrofolate to tetrahydrofolate. Since tetrahydrolfolate is required for purine and pyrimidine synthesis, methotrexate treatment results in the inhibition of DNA and RNA synthesis.
References
[1] J A M WESSELS H J G T W J Huizinga. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis.[J]. Rheumatology (Oxford, England), 2008: 249-255. DOI:
10.1093/rheumatology/kem279[2] CARMEN J. ALLEGRA. Evidence for direct inhibition of de novo purine synthesis in human MCF-7 breast cells as a principal mode of metabolic inhibition by methotrexate.[J]. The Journal of Biological Chemistry, 1987, 5 1: 13520-13526. DOI:
10.1016/s0021-9258(19)76458-8[3] E CHU. Mechanism of thymidylate synthase inhibition by methotrexate in human neoplastic cell lines and normal human myeloid progenitor cells.[J]. The Journal of Biological Chemistry, 1990, 265 15: 8470-8478.
[4] A H GERARDS. Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis.[J]. Rheumatology, 2003, 42 10: 1189-1196. DOI:
10.1093/rheumatology/keg323[5] BENJAMIN FRIEDMAN Bruce C. Methotrexate mechanism in treatment of rheumatoid arthritis[J]. Joint Bone Spine, 2019, 86 3: Pages 301-307. DOI:
10.1016/j.jbspin.2018.07.004[6] O’DELL J R. Therapeutic strategies for rheumatoid arthritis.[J]. New England Journal of Medicine, 2004, 350 25: 2591-2602. DOI:
10.1056/nejmra040226
