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.

Date of Award	1979
Original language	English