In a number of mammalian species, including man, the 4-amino analogs of pteroylglutamate persist in liver and kidney for many months after administration (1-4). In the rat (3) and mouse (4), the binding site appears to be the enzyme dihydrofolate reductase [also termed folate reductase (5) and tetrahydrofolate dehydrogenase.1] Studies with partially purified dihydrofolate reductase obtained from several sources (6-8) have shown the affinity of this enzyme for the 4-amino analogs to be extremely high.Recent work with tritium-labeled pteroylglutamate in vivo has shown that, in man, the labeled compound can be displaced from cells several days after its administration, both by unlabeled pteroylglutamate (9, 10) and by other compounds that possess an affinity for the enzyme dihydrofolate reductase (11). If, as animal experiments suggest, the 4-amino analogs bind to the same enzyme, a similar procedure should also bring about the displacement of these compounds. The studies reported here show that, in man, tritiated methotrexate (amethopterin; 4-amino-AN10-methylpteroylglutamic acid) can be readily displaced
A B S T R A C T Intestinal absorption of the monoglutamate form of the principal dietary and circulating folate compound, 5-methyltetrahydrofolic acid (5-MTHF), was studied in the rat utilizing a synthetic highly purified radiolabeled diastereoisomer. Chromatography confirmed that the compound was not altered after transfer from the mucosa to the serosa. Accumulation against a concentration gradient was not observed in duodenal, jejunal, or ileal segments at 5-MTHF concentration from 0.5 to 500 nmoles/liter. Unidirectional transmural flux determination also did not indicate a significant net flux. Mucosal to serosal transfer of 5-MTHF was similar in all segments of the intestine and increased in a linear fashion with increased initial mucosal concentrations. Further, no alteration in 5-MTHF transfer was found when studied in the presence of metabolic inhibitors or folate compounds.These results indicate that 5-MTHF is not absorbed by the rat small intestine by a carrier-mediated system and suggest that 5-MTHF transfer most likely represents diffusion. INTRODUCTIONThe mechanism of folate' absorption in man and experimental animal is not established. Both the paucity of
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