The effect of folate analogues and vitamin B12 on provision of thymine
nucleotides for DNA synthesis in megaloblastic anemia
MR Taheri, RG Wickremasinghe, BF Jackson and AV Hoffbrand
The role of vitamin B12 in the folate dependent biosynthesis of thymidine
nucleotides is controversial. In an attempt to clarify this, three methods
have been used to assess the relative efficacy of vitamin B12
(hydroxocobalamin) and various folate analogues in titrated concentrations
at correcting 'de novo' thymidylate synthesis by megaloblastic human marrow
cells: (1) The deoxyuridine (dU) suppression test which analyses the
reduction in (3H)-thymidine labeling of DNA by unlabeled dU. Marrow cells
were also labeled with (6-3H)-dU with assessment of (2) its incorporation
into DNA and (3) the accumulation of (6-3H)-deoxyuridine monophosphate
(3H-dUMP). The three methods gave similar results. In both, N6-formyl
tetrahydrofolate (formyl-FH4) was the most effective agent at correcting
thymidylate synthesis in megaloblastic anemia due to vitamin B12 or folate
deficiency. Vitamin B12 corrected the lesion in vitamin B12 deficiency but
not in folate deficiency. Tetrahydrofolate (FH4) and folic acid were
effective in deficiency of vitamin B12 or folate, although in both
deficiencies they were less effective than formyl-FH4. Methyl-FH4 was
effective in folate deficiency but not in vitamin B12 deficiency. These
results confirm the failure of methyl-FH4 utilisation in vitamin B12
deficiency. They suggest that if vitamin B12 is needed in the formylation
of FH4, this is a minor role in provision of the correct coenzyme for
thymidylate synthesis compared with its major role of provision of FH4 from
methyl- FH4.
Volume 59,
Issue 3,
pp. 634-640,
03/01/1982
Copyright © 1982 by The American Society of Hematology
