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Adverse effects of hyperhomocysteinemia and their management by folic acid
A F Perna1, N G De Santo, D Ingrosso
1Institute of Biochemistry of Macromolecules, Second University of Naples, Italy.
Insights
Elevated homocysteine in kidney disease patients contributes to cardiovascular risks. Folate treatment may help by lowering homocysteine and improving essential cellular repair processes.
Area of Science:
- Biochemistry
- Nephrology
- Cardiovascular Medicine
Background:
- Elevated plasma homocysteine is a significant risk factor for cardiovascular disease.
- Patients with chronic renal failure and uremia often exhibit hyperhomocysteinemia, a major contributor to their high cardiovascular mortality.
- Homocysteine toxicity impacts cellular methylation processes, crucial for molecular repair.
Purpose of the Study:
- To review homocysteine metabolism and toxicity mechanisms.
- To investigate the impact of hyperhomocysteinemia on protein methylation in renal failure patients.
- To explore the potential of folate therapy in ameliorating these effects.
Main Methods:
- Review of existing literature on homocysteine metabolism and toxicity.
- Analysis of erythrocyte membrane protein methylation levels in chronic renal failure and hemodialysis patients.
- Assessment of D-Asx concentrations as a marker for protein repair in hemodialysis patients.
Main Results:
- Homocysteine elevation increases intracellular adenosylhomocysteine, inhibiting vital transmethylation reactions.
- Reduced membrane protein methylation and defective repair of damaged proteins were observed in erythrocytes of renal failure and hemodialysis patients.
- Folate treatment was shown to significantly reduce plasma homocysteine levels.
Conclusions:
- Hyperhomocysteinemia in renal failure impairs essential protein repair mechanisms via reduced methylation.
- Folates, particularly methyltetrahydrofolate, show promise in improving transmethylation processes and potentially mitigating cardiovascular risks in these patients.
Abstract:
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.