Adverse effects of hyperhomocysteinemia and their management by folic acid.
A moderate increase in plasma homocysteine is an independent risk factor for cardiovascular disease. Plasma homocysteine is frequently elevated in chronic renal failure and in uremic patients, and the major causes of death in these patients are cardiovascular accidents. Homocysteine metabolism and mechanisms of toxicity are reviewed. Homocysteine elevation in blood leads to the intracellular increase of its precursor, adenosylhomocysteine, a powerful inhibitor of adenosylmethionine-dependent transmethylations. In vitro evidence shows that this increase is reversible upon homocysteine removal. Membrane protein methylation levels are consistently reduced in erythrocytes of both chronic renal failure and hemodialysis patients. This widespread enzymatic methylation is a key step for the repair of molecular damage resulting from the spontaneous deamidation and isomerization reactions of susceptible residues in proteins. In agreement with these findings is the observation that the concentration of a stable side product, D-Asx, of the repair process is significantly lower in erythrocyte membrane proteins from hemodialysis patients than from controls, showing that the repair of damaged membrane proteins is actually defective. It has been shown that treatment with folates dramatically lowers plasma homocysteine, presumably by improving remethylation to methionine. This indicates that folates and/ or their active derivative, i.e., methyltetrahydrofolate, could be effective in ameliorating transmethylations as well.
Perna
A F
AF
Institute of Biochemistry of Macromolecules, Second University of Naples, Italy.
De Santo
N G
NG
Ingrosso
D
D
D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy*; D005492:Folic Acid / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood; D008745:Methylation; D012307:Risk Factors; D014511:Uremia / Q000097:blood
D006710:Homocysteine; D005492:Folic Acid