Methotrexate Mechanisms and Effects

Introduction to Methotrexate

Methotrexate enters cells through specific transport mechanisms, including the solute carrier family 19, member 1 (SLC19A1), and can be actively transported out of cells by ATP-binding cassette transporters (ABCC1-4, ABCG2) 1
Methotrexate undergoes polyglutamation under the enzymatic control of folylpolyglutamate synthetase (FPGS), and polyglutamation is a dynamic process where glutamate residues can be removed by γ-glutamyl hydrolase (GGH) 1

Methotrexate inhibits dihydrofolate reductase (DHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC), leading to anti-inflammatory and immunosuppressive effects, as noted by the British Journal of Dermatology and the American Academy of Dermatology 2, 1
The polyglutamated forms of methotrexate have increased intracellular retention and enhanced anti-inflammatory activity, including the inhibition of thymidylate synthase (TYMS) and the increase in endogenous adenosine, which acts on adenosine receptors (ADORA A1 and 2a) producing anti-inflammatory effects 1

Methotrexate's anti-inflammatory effects, particularly through the inhibition of ATIC and the increase in adenosine, are important in the treatment of rheumatoid arthritis and psoriasis, as reported by the British Journal of Dermatology and the American Academy of Dermatology 2, 1
Low-dose methotrexate (<25 mg per week) primarily decreases proliferation of lymphoid cells, with a direct immunosuppressive effect being the main mechanism for improvement in psoriatic disease, according to the American Academy of Dermatology 2
Higher doses of methotrexate target rapidly dividing malignant cells, inhibiting DNA synthesis in actively proliferating tissues, and may overcome resistance caused by impaired active transport, decreased affinity of DHFR for methotrexate, increased levels of DHFR from gene amplification, and decreased polyglutamation, as noted by the British Journal of Dermatology 1

Understanding methotrexate's mechanisms of action explains why folic acid supplementation reduces side effects without significantly compromising efficacy, according to the American Academy of Dermatology 2
The efficacy and resistance patterns of methotrexate are affected by its transport into and out of cells, as noted by the British Journal of Dermatology 1