Metabolism and Handling of Folates in the Mammal Especially Man

Abstract

The metabolism of oral administered folates and their handling has been studied in humans. Aseptic addition methods of microbiological assay with L.casei, S.faecalis, P.cerevisiae and bioautographic techniques were employed in investigations of serum and urine folates. Studies of normal human serum and urine showed them to contain four folates, 5-methyltetrahydropteroylglutamic acid as the major folate, 5-methyl-5, 6-dihydropteroylglutamic acid, 10-formyltetrahydropteroylglutamic acid and 10-formylpteroylglutamicacid as minor folates. 10-formyltetrahydropteroylglutamicacid was maintained at a constant level by a homeostatic mechanism and 5-methyltetrahydropteroylglutamic acid acted as a storage form. Studies in rats and man showed that there was a diurnal variation of serum folates and folates in urine excretion. In some diseases even though total serum folates assayed with L.casei were in the normal range the three minor folates seemed to show abnormalities. In normal human volunteers there was rapid and almost complete metabolism in the serum to 5-methyltetrahydropteroylglutamic acid after oral administration of 7,8-dihydropteroylglutamicacid, 5-methyltetrahydropteroylglutamic acid, 5-formyltetrahydropteroylglutamicacid and 5,10-methenyltetrahydropteroylglutamicacid. Oral administration of pteroylglutamic acid itself gave a partial metabolism to 5-methyltetrahydropteroylglutamicacid whilst 10-formylpteroylglutamic acid remained unchanged. Oral administration of the oxidation products of 5-methyltetrahydropteroylglutamic acid showed that 5-methyl-5,6-dihydropteroylglutamic acid is partially utilized but mainly underwent rearrangement to microbiologically inactive5-methyl-5, 8-dihydropteroylglutamic acid in the stomach acid. Neutralization of stomach acid of normal humans with oral sodium bicarbonate enhanced the availability of 5-methyl-5,6-dihydropteroylglutamic acid and also in cases of achlorhydria of pernicious anaemia patients. This latter observation provides an alternative explanation of the elevated serum folate level found in pernicious anaemia. Other folates, 5-methyl-5, 8-dihydropteroylglutamicacid and 4a-hydroxy-5-methyl-ha, 5,6,7-tetrahydropteroylglutamic acid did not enter folate metabolic pool. Application of urine from these subjects to a Sephadex chromatograms suggested that they may be absorbed. It is established that the metabolism of oral folate was altered in some diseases. Malabsorption of 5-methyltetrahydropteroylglutamic acid was demonstrated in adult coeliac disease and leukaemia's. Oral folate metabolism in the presence of a dihydrofolate reductase inhibitor (methotrexate) administered orally 24 hour before the test was studied. No evidence could be found for a build up of dihydrofolic acid.