The "induction" of leukocyte and erythrocyte dihydrofolate reductase by methotrexate II. Clinical and pharmacologic studies

A study of the phenomenon of "induction" of the enzyme dihydrofolate reductase that occurs in leukocytes and erythrocytes after methotrexate administration has been made with the dog as an experimental model as well as man. The "induction" has been shown to be specific for 4-amino analogues of folate that are strong inhibitors of dihydrofolate reductase. Attempts to block induction with possible end products of dihydrofolate reductase activity and an inhibitor of protein synthesis, actinomycin D, were unsuccessful. Based upon studies of the enzymeinhibitor interaction as a function of pH, the rise in enzyme activity observed is explained by an accumulation of methotrexate-bound enzyme that occurs as a result of protection of the enzyme from normal catabolic processes; free enzyme is observed because of the in vitro conditions employed for enzyme assay.