From the Guidelines
Methotrexate is the drug that inhibits dihydrofolate reductase, affecting nucleotide synthesis. This mechanism is central to methotrexate's therapeutic effects in various conditions, as noted in the joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies 1. Dihydrofolate reductase is an enzyme that converts dihydrofolate to tetrahydrofolate, which is essential for the synthesis of thymidylate, purines, and several amino acids. By inhibiting this enzyme, methotrexate blocks the formation of tetrahydrofolate, leading to impaired DNA synthesis and cell division. This action particularly affects rapidly dividing cells, which explains methotrexate's effectiveness in treating cancers, autoimmune disorders like rheumatoid arthritis, and psoriasis.
The other listed medications work through different mechanisms:
- 5-fluorouracil inhibits thymidylate synthase
- Hydroxyurea inhibits ribonucleotide reductase
- Allopurinol inhibits xanthine oxidase in purine metabolism. The British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease also support the role of methotrexate in inhibiting dihydrofolate reductase 1. Furthermore, a review on the adverse effects of medications on micronutrient status highlights the importance of folate supplementation to reduce methotrexate-related toxicity 1.
Overall, the evidence consistently supports methotrexate as the drug that inhibits dihydrofolate reductase, affecting nucleotide synthesis, and this mechanism is crucial for its therapeutic effects in various conditions.
From the FDA Drug Label
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one- carbon groups in the synthesis of purine nucleotides and thymidylate.
The drug that inhibits dihydrofolate reductase, affecting nucleotide synthesis, is Methotrexate 2.
From the Research
Dihydrofolate Reductase Inhibition
- The drug that inhibits dihydrofolate reductase, affecting nucleotide synthesis, is Methotrexate 3, 4, 5, 6, 7.
Mechanism of Action
- Methotrexate works by inhibiting the enzyme dihydrofolate reductase (DHFR), which catalyzes the reduction of folate and 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate 4.
- This inhibition deprives rapidly dividing cells of reduced folates necessary for thymidylate synthesis and de novo purine nucleotide synthesis 5.
Resistance Mechanisms
- Cells can acquire resistance to Methotrexate through various mechanisms, including decreased uptake of the drug, decreased retention of the drug, increased enzyme activity, and decreased binding of Methotrexate to DHFR 4.
Clinical Significance
- Methotrexate is a widely used chemotherapeutic agent for the treatment of various cancers, including acute lymphocytic leukemia, osteosarcoma, and breast cancer 3, 4.
- Understanding the mechanisms of Methotrexate action and resistance is crucial for improving its efficacy and reducing toxicity 3, 4, 6, 7.