Metabolic consequences of folate-induced reduction of hyperhomocysteinemia in uremia.
Plasma homocysteine, a well-recognized risk factor for cardiovascular disease, is elevated in uremic patients on hemodialysis. The authors have recently demonstrated that one consequence is the reduction in red cell membrane protein methylation levels, caused by a rise of intracellular adenosylhomocysteine, a potent inhibitor of methyltransferases. Protein methylation is involved in a repair mechanism of damaged membrane proteins, and an impairment in methylation leads to the accumulation of altered proteins. Therapy with folates, cofactors in the transformation of homocysteine to methionine, is effective in lowering plasma homocysteine. This article details a study on the metabolic effects of oral methyltetrahydrofolate, the active form of folic acid, on 14 uremic hemodialysis patients. Two months of therapy led to a significant reduction of plasma homocysteine levels, with a proportional response to pre-folate levels. In five of 13 patients with homocysteine levels above 20 microM, plasma homocysteine level was reduced to less than 15 microM. After treatment, levels of adenosylmethionine, the methyl donor in transmethylations, had significantly increased; levels of adenosylhomocysteine had increased to a smaller extent. Therefore, the ratio between the two compounds, an excellent indicator of the presence and the degree of methylation inhibition, was significantly ameliorated. Methionine plasma levels increased after treatment in all patients and were correlated with posttreatment adenosylmethionine levels. It was concluded that treatment with methyltetrahydrofolate brings the plasma homocysteine concentration back to an "acceptable" level, and the metabolic consequences are in the direction of an increase in the normal flow of transmethylations, as monitored by an increase in the [adenosylmethionine]/[adenosylhomocysteine] ratio.
Perna
A F
AF
Institute of Biochemistry of Macromolecules, Department of Pediatrics, School of Medicine and Surgery, Second University of Naples, Italy.
Ingrosso
D
D
De Santo
N G
NG
Galletti
P
P
Brunone
M
M
Zappia
V
V
D004910:Erythrocyte Membrane / Q000378:metabolism; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008715:Methionine / Q000097:blood; D008745:Methylation; D008780:Methyltransferases / Q000097:blood; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood; D013763:Tetrahydrofolates / Q000494:pharmacology / Q000627:therapeutic use*; D014511:Uremia / Q000097:blood*
D008565:Membrane Proteins; D013763:Tetrahydrofolates; D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D008780:Methyltransferases; C005984:5-methyltetrahydrofolate