Methotrexate 59-05-2

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Molecular Weight:

454.44 Methotrexate is an antimetabolite and antifolate drug, which acts by inhibiting the Metabolism of folic acid.






Biological Activity


Methotrexate
(0.1-10 mM) induces Apoptosis of in vitro activated T cells from human
peripheral blood. Methotrexate achieves clonal deletion of activated T
cells in mixed lymphocyte reactions. Methotrexate can selectively delete
activated peripheral blood T cells by a CD95-independent pathway. Methotrexate is taken up by cells via the reduced folate carrier and
then is converted within the cells to polyglutamates.


Methotrexate leads
to diminished production of leukotriene B4 by neutrophils stimulated ex
vivo. Methotrexate polyglutamates inhibit the enzyme
aminoimidazolecarboxamidoadenosineribonucleotide (AICAR) transformylase
more potently than the other enzymes involved in purine biosynthesis.
Methotrexate is also known to suppress TNF activity by suppressing
TNF-induced nuclear factor-κB activation in vitro, in part related to a
reduction in the degradation and inactivation of an inhibitor of this
factor, IκBα, and probably related to the release of adenosine.


Methotrexate suppresses the production of both TNF and IFN-γ by
T-cell-receptor-primed T lymphocytes from both healthy human donors and
RA patients. Methotrexate treatment is associated with a significant
decrease of TNF-α-positive CD4+ T cells, while the number of T cells
expressing the anti-inflammatory cytokine IL-10 increased.


Methotrexate increases splenocyte AICAR content, raised adenosine
concentrations in exudates from carrageenan-inflamed air pouches, and
markedly inhibits leukocyte accumulation in inflamed air pouches in
mice. Methotrexate-mediated reduction in leukocyte accumulation is
partially reversed by injection of adenosine deaminase (ADA) into the
air pouch, completely reverses by a specific adenosine A2 receptor
antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), but not affected by
an adenosine A1 receptor antagonist, 8-cyclopentyl-dipropylxanthine in
mice.

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