Folate Metabolism in Normal and Tumour Bearing Mammals

Abstract

The whole animal metabolism and physiological disposition of folate derivatives has been studied in normal and tumour bearing rodents. Within 48 h of administration of radioactive folate tissue radioactivity was incorporated largely into high molecular weight folate conjugates. The major derivative was isolated from rat liver and identified as 10-formylfolate-y-tetraglutamate by spectral, microbiological, chemical and chromatographic techniques. A minor derivative exhibited similar properties and was assigned the structure 10-formylfolate-ytriglutamate. Similar conjugates were found in normal intestine and in the tumours and livers of Walker 256 tumour bearing rats. Urine collected 0-48 h after administration of folic acid, 10-formylfolate or 10-formylfolate-y-tetraglutamate contained several metabolites including both intact folates and folate catabolites. The major catabolite was identified as p-acetamidobenzoate by chromatography and reverse isotope dilution analysis and a reduced pteridine and folate derived CO, and urea also characterized. The relative amounts of intact folate “and folate catabolites varied with time and dose. Walker 256 tumour bearing rats excreted less intact folate and had markedly increased hepatic wp~ take, suggestive of tumour induced folate deficiency. A novel urinary pteridine derivative was excreted confirming the value of the folate pool as 4 potential source of tumour markers. A preliminary investigation of folate metabolism in male, female and immune-suppressed female mice was also made. The results presented support the existence of two metabolically distinct folate pools. The folate monoglutamates constitute the first pool, effectively functioning as a transport and short term storage form for the synthesis of the second pool - the folate polyglutamates - the active coenzymes. The folate in both pools is catabolised to simpler derivatives; the folate monoglutamates to p-acetemidobenzoate, probably by intestinal metabolism during enterohepatic circulation, and the folate polyglutamates to p-acetamidobenzoyl-L-glutamate and the unidentified pteridine in situ in the ceils.