Correction of the DNA synthesis defect in vitamin B12 deficiency by tetrahydrofolate: evidence in favour of the methyl-folate trap hypothesis as the cause of megaloblastic anaemia in vitamin B12 deficiency.
The critical disturbance of folate metabolism caused by vitamin B12 deficiency which results in megaloblastic anaemia remains controversial. Vitamin B12 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 B12 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 B12 deficiency as in folate deficiency. Although not as effective as formyl THF in correcting the dU blocking test in vitamin B12 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 B12 plays a critical role in folate metabolism.
Hoffbrand
A V
AV
Department of Haematology, Royal Free Hospital, School of Medicine, London.
Jackson
B F
BF
D000749:Anemia, Megaloblastic / Q000209:etiology*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D003857:Deoxyuridine; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D008297:Male; D008534:Megaloblasts / Q000378:metabolism; D013763:Tetrahydrofolates / Q000494:pharmacology / Q000502:physiology*; D013938:Thymidine Monophosphate / Q000096:biosynthesis; D014805:Vitamin B 12 / Q000494:pharmacology; D014806:Vitamin B 12 Deficiency / Q000150:complications* / Q000378:metabolism
D013763:Tetrahydrofolates; D013938:Thymidine Monophosphate; C030371:5,6,7,8-tetrahydrofolic acid; D004247:DNA; D014805:Vitamin B 12; D002955:Leucovorin; C005984:5-methyltetrahydrofolate; D003857:Deoxyuridine