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Correction of the DNA synthesis defect in vitamin B 12 deficiency by tetrahydrofolate: evidence in favour of the methyl‐folate trap hypothesis as the cause of megaloblastic anaemia in vitamin B 12 deficiency
Author(s) -
Hoffbrand A. V.,
Jackson B. F. A.
Publication year - 1993
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.1993.tb04704.x
Subject(s) - vitamin b12 , methionine synthase , megaloblastic anemia , methyltransferase , methionine , chemistry , cyanocobalamin , thymidylate synthase , medicine , biochemistry , endocrinology , methylation , dna , chemotherapy , fluorouracil , amino acid
Summary. The critical disturbance of folate metabolism caused by vitamin B 12 deficiency which results in megalo‐ blastic anaemia remains controversial. Vitamin B 12 is required in the methionine synthase reaction in which homocysteine is converted to methionine and methyl tetrahydrofolate (methyl THF) to THF. The ‘methyl‐folate trap’hypothesis suggested that failure of demethylation of methyl THF with consequent deficiency of folate co‐enzymes derived from THF is the crucial lesion caused by vitamin B 12 deficiency. A more recent theory suggested that reduced supply of methionine leads to reduced availability of ‘activated formate’and hence of formyl THF and it is this defect that results in failure of folate co‐enzyme synthesis. The present results, based on deoxyuridine suppression tests on 103 cases of megaloblastic anaemia, show that THF itself is equally capable of correcting the failure of thymidylate synthesis in vitamin B 12 deficiency as in folate deficiency. Although not as effective as formyl THF in correcting the dU blocking test in vitamin B 12 deficiency, this is equally so for the correction of the test by THF compared with formyl THF in folate deficiency. The results therefore favour the theory that it is in the supply of THF and not of ‘active formate’or formyl THF that vitamin B 12 plays a critical role in folate metabolism.