Defective DNA synthesis in human megaloblastic bone marrow: effects of homocysteine and methionine

Abstract

In B(12) deficiency, inadequate DNA synthesis seems due in large measure to a block of tetrahydrofolic acid (THFA) regeneration from 5-methyl THFA (via homocysteine transmethylation). In support of the above, homocysteine appears to facilitate and methionine to reduce de novo DNA synthesis. This was measured by the ability of deoxyuridine to suppress thymidine-(3)H uptake into DNA in human bone marrow cultures. The homocysteine effect in B(12)-deficient marrow supports the possibility that there is in man an additional B(12)-independent pathway for regeneration of THFA by methylation of homocysteine to form methionine. Among possible explanations for the methionine effect is end-product inhibition of the homocysteine transmethylase reaction, resulting in further accumulation of 5-methyl THFA. Homocysteine transmethylation may play an important role in the regulation of THFA availability and de novo DNA synthesis. In vitro and in vivo evidence suggests that methionine may be useful to potentiate and homocysteine to reduce methotrexate action.