RECOVERY OF LIVER TETRAHYDROFOLATE DEHYDROGENASE ACTIVITY FROM INHIBITION BY METHOTREXATE

Rat liver tetrahydrofolate dehydrogenase activity in vivo recovers rapidly from inhibition by methotrexate, despite the known stability of the enzyme-inhibitor complex. Control levels of activity are usually regained within 24 hr following a single injection of methotrexate. A similar pattern of recovery of activity has been found using the Guerin T8 epithelioma. Evidence that the enzyme is actually inhibited in situ has been obtained using a tetrazolium assay system. No evidence could be found for metabolism of the methotrexate to a form inactive with respect to tetrahydrofolate dehydrogenase. Synthesis of new enzyme with retention of the inhibited enzyme did not appear to play a major role in recovery of activity. Experiments using tritiated methotrexate indicated that both in vivo and in vitro, recovery of enzymic activity is probably associated with a dissociation of the enzyme-inhibitor complex. © 1969.