The cytotoxic effect of the vitamin B12 inhibitor cyanocobalamin [c-lactam], and a review of other vitamin B12 antagonists.
The vitamin B12 antagonist cyanocobalamin [c-lactam] was cytotoxic to cultured human leukemia cells, grown in methylfolate, homocysteine, and vitamin B12, but not in the presence of methionine. Small concentrations of methionine were effective in restoring the growth rate in a dose-dependent fashion, confirming methionine deficiency as the cytotoxic principle. Cyanocobalamin [c-lactam] prevented utilization of the methyl group of methylfolate, but no evidence of folate deficiency developed in long-term culture. High concentrations of non-methylated folate were unable to reverse the cytotoxicity, excluding a methylfolate 'trap' as the cause. Low concentrations of serine in the medium induced transient biochemical megaloblastosis. Cyanocobalamin [c-lactam] caused this to occur earlier, and persist. In high concentrations of serine, the inhibitor caused only transient changes in deoxyuridine suppression. Homocysteine cannot be remethylated without vitamin B12, and condensation with serine is the only other excretory pathway for this toxic amino acid. We hypothesize that impaired DNA synthesis in vitamin B12 deficiency is the result of diverting serine away from thymidylate synthesis, into homocysteine metabolism.
Department of Medicine, Queen's University, Kingston, Ontario, Canada. matthewj@post.queensu.ca
J H
JH
Matthews
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy*; D016014:Linear Models; D016015:Logistic Models; D008765:Methylmalonyl-CoA Mutase / Q000187:drug effects; D013329:Structure-Activity Relationship; D014805:Vitamin B 12 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D008765:Methylmalonyl-CoA Mutase; D014805:Vitamin B 12