The Cytotoxic Effect of the Vitamin B₁₂ Inhibitor Cyanocobalamin [c-lactam], and a Review of Other Vitamin B₁₂ Antagonists

Abstract

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 mega-loblastosis. 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.

Key Words:

• Vitamin B₁₂
• methionine
• homocysteine
• HL-60 Cells
• enzyme inhibitors
• folic acid
• methylmalonyl-CoA
• methionine synthase