Metabolic consequences of folate-induced reduction of hyperhomocysteinemia in uremia.

Institute of Biochemistry of Macromolecules, Department of Pediatrics, School of Medicine and Surgery, Second University of Naples, Italy.
Journal of the American Society of Nephrology (Impact Factor: 9.47). 01/1998; 8(12):1899-905.
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: Chronic nutritional deficiencies in folate, choline, methionine, vitamin B-6 and/or vitamin B-12 can perturb the complex regulatory network that maintains normal one-carbon metabolism and homocysteine ho-meostasis. Genetic polymorphisms in these pathways can act synergistically with nutritional deficiencies to accelerate metabolic pathology associated with occlusive heart disease, birth defects and dementia. A major unanswered question is whether homocysteine is causally involved in disease pathogenesis or whether homocys-teinemia is simply a passive and indirect indicator of a more complex mechanism. S-Adenosylmethionine and S-adenosylhomocysteine (SAH), as the substrate and product of methyltransferase reactions, are important metabolic indicators of cellular methylation status. Chronic elevation in homocysteine levels results in parallel increases in intracellular SAH and potent product inhibition of DNA methyltransferases. SAH-mediated DNA hypomethylation and associated alterations in gene expression and chromatin structure may provide new hypoth-eses for pathogenesis of diseases related to homocysteinemia. J. Nutr. 132: 2361S–2366S, 2002. KEY WORDS: ● homocysteine ● S-adenosylhomocysteine ● S-adenosylmethionine ● DNA methylation Regulatory determinants of homocysteine metabolism The sole intracellular source of homocysteine (Hcy) 3 is the hydrolysis of S-adenosylhomocysteine (SAH) by the enzyme SAH hydrolase (SAHH; EC (1,2). Of the four en-zymes capable of metabolizing Hcy, only the SAHH reaction is readily reversible (Fig. 1). Methionine synthase [MS(5-methyltetrahydrofolate-homocysteine S-methyltransferase); EC] and betaine-homocysteine methyltransferase (BHMT; EC both remethylate Hcy to methionine, and both are unidirectional. Similarly, the permanent removal of Hcy from the methionine cycle by cystathionine ␤-synthase (CBS; EC is a one-way reaction. Although the equilibrium dynamics of the SAHH reaction strongly favor SAH synthesis over Hcy synthesis, the efficient metabolic removal of Hcy and adenosine by the multiple pathways in-dicated in Figure 1 allows sustained Hcy synthesis to predom-inate (3). Remethylation of Hcy to methionine (the methio-nine cycle) predominates over the catabolic degradation of Hcy (transsulfuration) because of the order of magnitude dif-ference in K m between MS and CBS (1). Genetic or nutri-tional perturbations that hinder efficient product removal of Hcy or adenosine will induce reversal of the SAHH reaction, leading to an intracellular accumulation of SAH (4). Chronic deficiencies in the nutrients folate, vitamin B-12, vitamin B-6, methionine or choline can independently and interactively disrupt normal metabolic flow and increase Hcy. Excess free intracellular Hcy is thought to readily cross the cell membrane into the plasma, although the precise mechanism is not known. Genetic polymorphisms in genes coding for enzymes in-volved in these pathways interact with nutritional deficiencies to magnify imbalances in one-carbon metabolism that may promote several chronic disease states in humans (5,6). Gene-nutrient interactions that elevate Hcy levels have been asso-ciated with increased risk of cardiovascular disease (7), colon cancers (8), birth defects (9,10), recurrent early pregnancy loss (11), central nervous system (CNS) demyelinization (12) and neuropsychiatric disease (13,14). Most recently, an increment of 5 ␮M plasma Hcy was associated with a 49% increase in
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    Seminars in Dialysis 03/2003; 16(2). · 2.25 Impact Factor

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