Abstract
Methotrexate (MTX) is generally believed to be a potent inhibitor of dihydrofolate reductase (DHFR),inhibition of this enzyme leading to cell death.However,the intracellular binding of MTX to DHFR was found by a cytochemical method to be weak and reversible. Thus MTX was readily displaced by the physiological substrate,dihydrofolate (FH2). The displacement of MTX by FH2 has been confirmed by experiments in mice. A group of 68 AKR mice was studied ,8-12 weeks old (12-26 g). MTX was injected i.p. in the lethal dose of 200 mg or 300 mg/ kg FH2 was injected in the same doses as MTX prior or simultaneously or up to 72 hrs after MTX. The younger and lighter mice survived when FH2 was given 1 hr prior to the lethal dose of MTX, and the older and heavier mice survived even when FH2 was given up to 17 hrs after MTX. These results suggest that FH2 reversed the toxicity of a lethal dose of MTX and protected the animals when equal amounts of FH2 were given 1 hr before or simultaneously or up to 17 hrs after MTX.
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Tzortzatou, F. Reversibility of the toxicity of methotrexate by dihydrofolate in mice. Pediatr Res 13, 73 (1979). https://doi.org/10.1203/00006450-197901000-00024
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DOI: https://doi.org/10.1203/00006450-197901000-00024