The purpose of this study was to determine whether the activity of dihydrofolate reductase (5,6,7,8-tetrahydrofolate: NADP oxidoreductase, EC 126.96.36.199) in liver, kidney and small intestine of mice given sublethal amounts of methotrexate at weekly intervals could be modified by the concomitant administration of either folic acid, N5-formyltetrahydrofolic acid or N5-methyltetrahydrofolic acid. The folate compounds were administered to separate groups of BDF1 mice 6 days after each group received methotrexate (3 mg/kg) and 24 hr preceding the subsequent injection of the drug. The administration of N5-formyltetrahydrofolic acid increased the accumulation of methotrexate in the liver, kidney and small intestine. N5-methyltetrahydrofolic acid increased the methotrexate accumulation in kidney and small intestine but not in the liver. Folic acid administration did not affect the accumulation of methotrexate in any of these tissues. The liver, kidney and small intestine of mice receiving methotrexate alone, as expected, contained lower dihydrofolate reductase activity. This decrease in enzyme activity in these tissues was not observed if the mice also received folic acid and N5-methyltetrahydrofolic acid. N5-formyltetrahydrofolic acid, which similarly prevented the decrease in dihydrofolate reductase activity in the kidney, had no such effect on enzyme activity in liver and small intestine. These studies demonstrate that the accumulation of methotrexate and/or the activity of dihydrofolate reductase after repetitive sublethal administration of the drug can be modified by the administration of folic acid and reduced folates. If the toxicity to normal tissues which occurs with chronic nonmyelotoxic doses of methotrexate is secondary to depressed activity of dihydrofolate reductase, the periodic administration of a folate compound which raises the activity of this enzyme may be beneficial.
|Number of pages||4|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - 1982|