Studies of Folate Metabolism in Man and the Rat

Abstract

The metabolism of a mixture of [2-14C] and [3', 5', 7' ,9-3H]-folic acid was studied in man and the rat. Similar observatfons were found in both species. Folic acid is metabolised to vartous compounds. Both intact folates and folate catabolites were excreted in the urine after administration and folate polyglutamatesfound in the tissues. The relative amounts of intact folates and folate catabolites varied with time and dose. The results presented support the existence of two metabolically distinct pools, a shortterm pool with a half-life of approximately one day and a long-term pool with a half-life of 11 days and demonstrate that the breakdown of folate in vivo is a function of normal folate metabolism. Patients with malignant disease and tumour-bearing rats excreted less of the dose in the urine, incorporated more into the reduced folate pool and showed decreased catabolism of folate when compared to controls. The administration of methotrexate to rats increased the catabolic rate of folate and the excretion of radioactivity in the urine and caused a corresponding fall in the levels of radioactivity recovered in the tissues. Methotrexate also led to the excretion of 4 additional radioactive pterins not found in normal urine. The induction of the hepatic enzymes by phenobarbitone failed to increase the catabolic rate of folate. The possible mechanism of folate breakdown in the tissues has been elucidated to be a simple chemical oxidative cleavage of the C9- N10, bond of labile folate derivatives produced during the normal metabolic  pathways. The metabolism of 10 formylfolate was also studied in man. It is excreted largely unchanged in the urine and appears not to be reduced by man. 10 Formylfolate enters the reduced folate pool extremely slowly via deformylation. Also, 10 formylfolate inhibits the reduction of folic acid in vivo.