Unbalanced deoxyribonucleotide synthesis caused by methotrexate.

The effect of methotrexate on the free intracellular pools of thymidylate triphosphate (dTTP) and deoxyadenosine triphosphate (dATP) in normal human phytohaemagglutinin-transformed lymphocytes has been studied. Methotrexate caused a fall in the dTTP pool ranging from 38% to 88% and a rise in the dATP pool ranging from 24% to 185%.A rise in the free intracellular pool of dATP is thought to inhibit both rubonucleotide reduction and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair. The hypothesis is suggested here that folate deficiency per se, as well as a functional folate deficiency induced by methotrexate may cause reduced DNA synthesis, megaloblastic changes, and chromosome abnormalities by producing a rise in the free intracellular pool of dATP as well as by causing a fall in free intracellular dTTP.