The recovery of liver tetrahydrofolate dehydrogenase activity from inhibition by methotrexate

Abstract

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.