Homocysteine Catabolism Research Articles

Interrelationship between diabetes and homocysteine metabolism: hormonal regulation of cystathionine beta-synthase.

Plasma homocysteine levels are elevated during diabetes when there is atherosclerosis or insufficient renal function; however, diminished plasma homocysteine concentrations are observed in diabetes without complications. Recent studies have demonstrated that under diabetic conditions, the catabolism of homocysteine was enhanced by transcriptional regulation of hepatic cystathionine beta-synthase and these changes were prevented by treatment with insulin.

Vitamin B12 decreases, but does not normalize, homocysteine and methylmalonic acid in end-stage renal disease: A link with glycine metabolism and possible explanation of hyperhomocysteinemia in end-stage renal disease

The genetic and environmental factors influencing catabolism of homocysteine in end-stage renal disease (ESRD) patients remain poorly understood. This study investigated how genetic and nutritional influences affect the response to high-dose vitamin B12 and folate treatment in ESRD patients with hyperhomocysteinemia. We studied 81 hemodialysis patients with hyperhomocysteinemia (> 16 μmol/L) on varied doses of a multivitamin containing 1 mg of folic acid per day. After screening blood work, all patients were switched to daily multivitamin therapy including 1 mg of folic acid for 4 weeks. Vitamin B12, 1 mg/d, was added for an additional 4 weeks. Patients were then randomized to receive folic acid or placebo. The influence of the 3 methylenetetrahydrofolate reductase (MTHFR) 677 C→T genotypes on the efficacy of vitamin therapy was assessed. In addition, we investigated how the metabolic complications of ESRD, including the relationship between methylmalonic acid (MMA) and circulating glycine, may contribute to hyperhomocysteinemia. There was no significant difference in total homocysteine (tHcy) levels between the MTHFR 677 C→T genotypes during the screening phase of the trial. Treatment with a daily multivitamin containing 1 mg folate significantly lowered tHcy levels in all patients by 19.2%. Further supplementation with 1 mg vitamin B12 resulted in greater tHcy reduction among subjects with the MTHFR 677 T/T genotype (P<.01, T/T v C/C or C/T) while lowering MMA equally in all MTHFR genotypes. There was a significant positive correlation between plasma glycine levels and MMA (P <.05). High-dose vitamin therapy significantly lowers, but does not normalize, MMA and tHcy levels. The MTHFR genotype, while influencing homocysteine levels, was not responsible for the majority of the elevation in plasma tHcy. Copyright 2003, Elsevier Science (USA). All rights reserved.

Crystallization and preliminary X-ray study of recombinant betaine-homocysteine S-methyltransferase from rat liver.

Betaine-homocysteine S-methyltransferase is one of the three enzymes involved in homocysteine catabolism. It uses betaine as the methyl donor to convert homocysteine into methionine, also producing dimethylglycine. Recombinant BHMT from rat liver was crystallized by the vapour-diffusion method in both native and seleniomethionyl-labelled forms. Crystals belong to space group P2(1), with unit-cell parameters a = 57.8, b = 149.3, c = 96.2 A, beta = 92.9 degrees. Data from native, seleniomethionine-labelled and two heavy-atom derivatives were collected using synchrotron sources. Self-rotation function and sedimentation-velocity experiments suggest that the enzyme is tetrameric with 222 symmetry.

Possible involvement of sulfane sulfur in homocysteine-induced atherosclerosis

Homocysteinemia, first identified as a genetic disease in children in the 1960s, is associated with severe widespread atherosclerosis which causes death (in untreated cases) before the age of 10 years. Elevated blood homocysteine is now recognized as a risk factor for heart disease in the general population. The mechanism by which homocysteine induces atherosclerosis is still unknown despite intensive investigation. It is proposed here that the mechanism involves sulfane sulfur formed in the catabolism of homocysteine. This unstable and reactive form of sulfur is formed through the action of several enzymes which are known to use homocysteine, its disulfide (homocystine), or its mixed disulfide with cysteine as substrates. Sulfane sulfur has physiological effects which are consistent with a role in atherogenesis. At very low concentrations, it induces proliferation of many cell types, an effect which is consistent with the fibrosis and hyperplasia, which are prominent features of atherosclerotic lesions. At higher concentrations, it is toxic. Also, it modulates the activity of many enzymes and, through this effect on enzymes of lipid metabolism, it could be responsible for the lipid accumulation seen in atherosclerotic lesions.

Vitamin B-6 Deficiency in Rats Reduces Hepatic Serine Hydroxymethyltransferase and Cystathionine β-Synthase Activities and Rates of In Vivo Protein Turnover, Homocysteine Remethylation and Transsulfuration

Vitamin B-6 deficiency causes mild elevation in plasma homocysteine, but the mechanism has not been clearly established. Serine is a substrate in one-carbon metabolism and in the transsulfuration pathway of homocysteine catabolism, and pyridoxal phosphate (PLP) plays a key role as coenzyme for serine hydroxymethyltransferase (SHMT) and enzymes of transsulfuration. In this study we used [(2)H(3)]serine as a primary tracer to examine the remethylation pathway in adequately nourished and vitamin B-6-deficient rats [7 and 0.1 mg pyridoxine (PN)/kg diet]. [(2)H(3)]Leucine and [1-(13)C]methionine were also used to examine turnover of protein and methionine pools, respectively. All tracers were injected intraperitoneally as a bolus dose, and then rats were killed (n = 4/time point) after 30, 60 and 120 min. Rats fed the low-PN diet had significantly lower growth and plasma and liver PLP concentrations, reduced liver SHMT activity, greater plasma and liver total homocysteine concentration, and reduced liver S-adenosylmethionine concentration. Hepatic and whole body protein turnover were reduced in vitamin B-6-deficient rats as evidenced by greater isotopic enrichment of [(2)H(3)]leucine. Hepatic [(2)H(2)]methionine production from [(2)H(3)]serine via cytosolic SHMT and the remethylation pathway was reduced by 80.6% in vitamin B-6 deficiency. The deficiency did not significantly reduce hepatic cystathionine-beta-synthase activity, and in vivo hepatic transsulfuration flux shown by production of [(2)H(3)]cysteine from the [(2)H(3)]serine increased over twofold. In contrast, plasma appearance of [(2)H(3)]cysteine was decreased by 89% in vitamin B-6 deficiency. The rate of hepatic homocysteine production shown by the ratio of [1-(13)C]homocysteine/[1-(13)C]methionine areas under enrichment vs. time curves was not affected by vitamin B-6 deficiency. Overall, these results indicate that vitamin B-6 deficiency substantially affects one-carbon metabolism by impairing both methyl group production for homocysteine remethylation and flux through whole-body transsulfuration.

Homocysteine as a Cardiovascular Risk Factor

Hyperhomocysteinemia (HH), a known risk factor for vascular diseases, is a frequent condition in hemodialysis (HD) patients. HH induces an oxidant stress to the vascular endothelium, causing a failure of vasodilation and an impairment of the antithrombotic properties. Vitamins B₆, B₁₂ and folic acid are important cofactors for the enzymes in the catabolism of homocysteine (Hcy). Failure of Hcy catabolism forces the cell to export Hcy into the plasma. The kidney is an important metabolic site for removal (up to 70%) of plasma Hcy (P-Hcy). HD lowers the P-Hcy concentration by 29 and 41% with cellulosic and noncellulosic membranes, respectively, yet values return to normal in only a few patients. Clearly, we must decrease the dangerous high levels of Hcy in different ways. Vitamin Supplementation: Vitamins B₆, B₁₂ and folic acid decreased the basal level of Hcy by about 40%, starting from the sixth month. Membranes: Some membranes performed better than the others. Techniques: On the chronic basis, in our 1-year experience, paired filtration dialyis led to the best results, when compared to bicarbonate dialysis and acetate-free biofiltration. Finally, as in HD patients no one type of treatment can normalize the P-Hcy concentration, we should try other, different strategies such as absorption, the use of liposomes and new types of supplementation.

Pathways and regulation of homocysteine metabolism in mammals.

Two intersecting pathways, the methionine cycle and the transsulfuration sequence, compose the mechanisms for homocysteine metabolism in mammals. The methionine cycle occurs in all tissues and provides for the remethylation of homocysteine, which conserves methionine. In addition, the cycle is essential for the recycling of methyltetrahydrofolate. The synthesis of cystathionine is the first reaction in the irreversible pathway for the catabolism of homocysteine by means of the sequential conversion to cysteine and sulfate. This pathway has a limited distribution and is found primarily in the liver, kidney, small intestine and pancreas. Regulation of homocysteine metabolism is achieved by changes in the quantity of homocysteine distributed between the two competing pathways. Two mechanisms are basic to the regulatory process. Changes in tissue content of the relevant enzymes are the response to sustained perturbations. The inherent kinetic properties of the enzymes provide an immediate response to alterations in the tissue concentrations of substrates and other metabolic effectors. S-adenosylmethionine, S-adenosylhomocysteine, and methyltetrahydrofolate are of particular importance in that context.

Oxidants downstream from superoxide inhibit nitric oxide production by vascular endothelium – a key role for selenium-dependent enzymes in vascular health

Although superoxide can directly quench endothelium-generated nitric oxide (NO), there is considerable evidence that oxidants derived from superoxide – notably peroxides and their further derivatives – can also impair NObioactivity. In part, this reflects inhibition of NO synthase activity, perhaps mediated by the oxidation of labile sulfhydryl groups, as well as the activation of protein kinase C. Selenium deficiency exacerbates these effects, presumably owing to the crucial role of selenium-dependent thioredoxin reductase and glutathione peroxidases in preventing and reversing oxidant damage to proteins. High–normal homocyst(e)ine levels may induce an ‘effective selenium deficiency’' by suppressing glutathione peroxidase transcription in endothelial cells. Considerable epidemiology, primarily of European origin, points to mediocre selenium nutrition as a significant vascular risk factor; the risk associated with elevated plasma homocyst(e)ine levels is now well established. In addition to preventing LDL oxidation, vitamin E can be expected to minimize the contribution of lipid peroxides to endothelial dysfunction. Lipoic acid, which can function in vivo as a versatile antioxidant and sulfhydryl reductant, may have particular value for protecting endothelium from oxidants; its clinical utility in diabetic neuropathy may reflect this benefit. Good selenium status, as well as supra-nutritional intakes of lipoic acid, may down-regulate cytokine-mediated endothelial activation by helping to maintain the proper structure of oxidant-labile proteins – such as tyrosine phosphatases – that modulate this signaling. It can be concluded that a number of supplemental nutrients – including selenium, vitamin E, lipoic acid, and the vitamins that promote catabolism of homocysteine – have the potential to promote vascular health by mitigating the adverse impact of superoxide-derived oxidants on endothelial function

Effects of streptozotocin-induced diabetes and of insulin treatment on homocysteine metabolism in the rat.

An elevation in the concentration of total plasma homocysteine is known to be an independent risk factor for the development of vascular disease. Alterations in homocysteine metabolism have also been observed clinically in diabetic patients. Patients with either type 1 or type 2 diabetes who have signs of renal dysfunction tend to exhibit elevated total plasma homocysteine levels, whereas type 1 diabetic patients who have no clinical signs of renal dysfunction have lower than normal plasma homocysteine levels. The purpose of this study was to investigate homocysteine metabolism in a type 1 diabetic animal model and to examine whether insulin plays a role in its regulation. Diabetes was induced by intravenous administration of 100 mg/kg streptozotocin to Sprague-Dawley rats. We observed a 30% reduction in plasma homocysteine in the untreated diabetic rat. This decrease in homocysteine was prevented when diabetic rats received insulin. Transsulfuration and remethylation enzymes were measured in both the liver and the kidney. We observed an increase in the activities of the hepatic transsulfuration enzymes (cystathionine beta-synthase and cystathionine gamma-lyase) in the untreated diabetic rat. Insulin treatment normalized the activities of these enzymes. The renal activities of these enzymes were unchanged. These results suggest that insulin is involved in the regulation of plasma homocysteine concentrations by affecting the hepatic transsulfuration pathway, which is involved in the catabolism of homocysteine.

Saudi Experience with Classic Homocystinuria

Classic homocystinuria is an autosomal recessive disorder due to cystathionine ss-synthase deficiency. The clinical, radiological and neurophysiological findings of classic homocystinuria diagnosed at King Faisal Specialist Hospital and Research Centre (KFSH&RC) are presented in this report. Twenty-four patients (15 females and 9 males) were referred to KFSH&RC for work-up of mental retardation, seizures, thrombo-embolic episodes and dislocation of the ocular lenses. The common clinical findings included ectopia lentis (20 patients), skeletal system involvement (18 patients), vascular system involvement (9 patients), and mental retardation (all patients to varying degrees). Unusual findings consisted of a patient who developed severe lower gastrointestinal bleeding, a patient with insulin-dependent diabetes mellitus, probably due to vasculopathy, and another having severe bronchiectasis, which may have been due to fibrillin disruption, and required the resection of a lobe of the lung. The parents of 21 patients were first-degree relatives, and 19 patients had one or more family members affected by the same disease. All patients had markedly elevated plasma levels of methionine. Cystathionine synthase activity in the fibroblast was measured in 25% of the patients and was deficient. Only four patients responded to pyridoxine and their methionine level decreased to almost normal range. The aim of this study was to increase the awareness of this disease in the scientific and medical community, in particular in the general pediatrician working in Saudi Arabia who first encounters the clinical manifestations of the disease. Early detection through tandem mass spectrometry of blood spot screening and treatment are important, and may prevent the major complications of this disease.

The effect of renal transplantation on hyperhomocysteinaemia in dialysis patients, and the estimation of renal homocysteine extraction in patients with normal renal function

Background: The pathophysiology of hyperhomocysteinaemia in chronic renal failure (CRF) is unknown. Possible mechanisms are decreased renal homocysteine (Hcy) catabolism or inhibition of extrarenal Hcy metabolism by uraemic toxins.Methods: We studied the short-term effect on plasma Hcy concentration of improvement of renal function after successful kidney transplantation (n=8), and determined renal Hcy extraction by measurement of total Hcy in arterial and renal venous blood in 7 cardiac patients with normal renal function.Results: Post-transplantation, plasma Hcy decreased with improving renal function. In the cardiac patients, no significant renal Hcy extraction could be demonstrated, but tubular disposal of the filtered load could not be excluded.Conclusions: Because loss of such renal metabolism could lead to hyperhomocysteinaemia in CRF, it is necessary to determine the renal extraction of free Hcy in subjects with normal renal function to further investigate renal homocysteine metabolism.

Simplified Simultaneous Assay of Total Plasma Homocysteine and Methionine by HPLC and Pulsed Integrated Amperometry

Measurement of total plasma homocysteine (tHcy) can be a useful adjunct in the diagnosis of cobalamin or folate deficiency and is emerging as an independent predictor in many vaso-occlusive diseases (1). As clinical interest in this metabolite grows, the demand for simple and efficient methods of determination has increased. In some situations, a methionine-loading test may be conducted to evaluate homocysteine catabolism, but methionine is rarely measured concomitantly, because it usually requires a different assay methodology altogether. In homocystinuria caused by cystathionine beta-synthase deficiency, circulating methionine is often increased, whereas homocystinuria resulting from a relative deficiency of the remethylation pathway is characterized by hypomethioninemia (2). In our previously reported serum assay for tHcy (3), we used the DX-500 Ion Chromatograph (Dionex Canada), outfitted with two pumps (in parallel), valves, and two columns (a 4 × 50 mm OmniPac PCX-500 precolumn and a 4 × 250 mm OmniPac PCX-500 analytical column) plumbed in series to permit “heart-cut” trapping of tHcy (4). However, with the ED40 electrochemical detector set for pulsed integrated amperometry (PIA) mode, any compound with a reduced sulfur atom, including methionine, will generate a signal proportional to concentration (5). In our initial procedure, the disulfide reduction procedure with sodium borohydride (NaBH4) (6) was the most labor-intensive step and constituted a substantial source of …

VPA‐induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

Valproate (VPA) has been shown to induce neural tube defects (NTDs) in humans and mice, but the mechanism of action has not been elucidated. Folate supplementation has been reported to prevent the defect. It was the aim of our experiment to reveal effects of VPA and of folate coadministration on amino acid metabolism in an NTD mouse model. After treating pregnant mice intraperitoneally with 2.1 mmol VPA/kg body weight, plasma homocysteine concentrations were found to be increased. Coadministration of 4 mg/kg folate decreased this level. Plasma methionine levels were reduced under both experimental conditions. Fifteen min after treating mice with 3 mmol VPA/kg body weight, hepatic levels of both S-adenosylmethionine (SAM) and S-adenosylhomocysteine were found to be increased by +175% and +348%, respectively; but the levels had normalized again 30 min after VPA injection. Simultaneously, plasma methionine and serine levels had decreased by –43% and –51%, respectively, while homocysteine and cysteine increased by +71% and +81%, respectively. Reduced glutathione (GSH) decreased by –45%, but total glutathione did not change. These changes were statistically significant, and they occurred dose-dependently. We proposed that VPA induces methionine deficiency, inhibition of folate metabolism and homocysteine remethylation, increase in aminothiols, and suppression of the GSH system in maternal blood within 1 h after application. These changes may be responsible for the teratogenic potential of VPA. Folate may prevent NTDs by changing homocysteine catabolism. Teratogenesis Carcinog. Mutagen. 18:49–61, 1998. © 1998 Wiley-Liss, Inc.

VPA-induced neural tube defects in mice. I. altered metabolism of sulfur amino acids and glutathione

Valproate (VPA) has been shown to induce neural tube defects (NTDs) in humans and mice, but the mechanism of action has not been elucidated. Folate supplementation has been reported to prevent the defect. It was the aim of our experiment to reveal effects of VPA and of folate coadministration on amino acid metabolism in an NTD mouse model. After treating pregnant mice intraperitoneally with 2.1 mmol VPA/kg body weight, plasma homocysteine concentrations were found to be increased. Coadministration of 4 mg/kg folate decreased this level. Plasma methionine levels were reduced under both experimental conditions. Fifteen min after treating mice with 3 mmol VPA/kg body weight, hepatic levels of both S-adenosylmethionine (SAM) and S-adenosylhomocysteine were found to be increased by +175% and +348%, respectively; but the levels had normalized again 30 min after VPA injection. Simultaneously, plasma methionine and serine levels had decreased by -43% and -51%, respectively, while homocysteine and cysteine increased by +71% and +81%, respectively. Reduced glutathione (GSH) decreased by -45%, but total glutathione did not change. These changes were statistically significant, and they occurred dose-dependently. We proposed that VPA induces methionine deficiency inhibition of folate metabolism and homocysteine remethylation, increase in aminothiols, and suppression of the GSH system in maternal blood within 1 h after application. These changes may be responsible for the teratogenic potential of VPA. Folate may prevent NTDs by changing homocysteine catabolism.

Vitamin therapy of hyperhomocysteinaemia in chronic renal failure

s 1933 Vitamin therapy of hyperhomocysteinaemia in chronic renal failure M. Hages, K. Pietrzik Institut fur Ernahrungswissenschaft, Abt. Pathophysiologie der Ernahrung des Menschen. Rheinische Friedrich-Wilhelms-Universitat. Bonn, Germany In patients with chronic renal failure, plasma homocysteine levels are already elevated significantly at an early stage and show a negative correlation with the glomerular filtration rate and serum creatinine concentration, respectively. End-stage renal disease patients on dialysis have homocysteine levels threeor fourfold above normal [1,2]. In several studies moderate hyperhomocysteinemia has been identified as a potential independent risk factor for premature cardiovascular disease, a frequent complication of advanced renal diseases. The mechanism of the atherogenic action of homocysteine is not clearly understood, but it is theorized that homocysteine is cytotoxic to the endothelial wall and promotes the oxidative modification of LDL cholesterol [3]. The elevated homocysteine concentration in patients with renal failure is mainly caused by the decreased catabolism of homocysteine in the proximal tubular cells due to reduced filtration and to tubular dysfunction. Additionally, the extrarenal homocysteine metabolism is decreased due to inhibition by retained metabolites [4]. Homocysteine is an amino acid, which is formed as an intermediate in the metabolism of methionine. Homocysteine can be remethylated to methionine with folic acid as methyl-donor and vitamin B12 as co-factor. Additionally, it can be converted to cystathionine by condensation with serin in an irreversible reaction. This metabolic step requires vitamin B6 as cofactor. The status of vitamin B6, B12, and folic acid is regarded as an important factor influencing the homocysteine level. However, many renal patients with elevated homocysteine concentrations have normal baseline serumand red cell folate levels, as well as normal serum B12 and B6 concentrations. Therefore, it is unlikely that manifest vitamin deficiencies contribute to the elevated homocysteine levels in patients with uraemia and end-stage renal disease. Nevertheless, the folic acid and vitamin B12 status in these patients is negatively correlated with their plasma homocysteine concentration [5,6]. Patients with renal failure, especially dialysis patients, frequently show vascular dysfunction as manifested by an elevated plasma level of von-Willebrand factor (vWF)-antigen, which is reported to be one of the specific markers of endothelial activation and inflammation. The elevated concentration of this indicCorrespondence and offprint requests to: M. Hages, Institut fur Ernahrungswissenschaft, Abt. Pathophysiologie der Ernahrung des Menschen, Rheinische Friedrich-Wilhelms-Universitat, Bonn, Germany. ator of endothelial damage is not only due to the reduced clearance in renal failure because there is no correlation between GFR and the blood level of this factor. Moreover, the level of von-Willebrand factor antigen in dialysis patients is negatively correlated with the duration (years) of hemodialysis [7]. These observations suggest the possibility of endothelial injury. There is in-vitro evidence that homocysteine promotes the release of von-Willebrand factor antigen [8]. However, in most studies, the fasting homocysteine plasma concentration and von-Willebrand factor don't correlate [9]. But after methionine loading test (0.1 g methionine/kg BW), the post-load homocysteine levels showed a significant relationship to the endothelial function parameter [9]. A methionine loading test stresses the pathway involved in homocysteine metabolism and is a valid diagnostic test for an abnormal homocysteine handling. Treatment with high doses of folic acid (5 mg/d) significantly lowers [10,11] the elevated homocysteine concentrations, both in non-dialyzed and in haemodialyzed patients, by the stimulation of the remethylation of homocysteine. This can be observed even in the absence of evident folate deficiency. In patients with mild hyperhomocysteinaemia and peripheral arterial occlusive disease, the vitamin is also able to reduce the elevated levels of von-Willebrand factor and appears to ameliorate the endothelial function [9]. Corresponding studies with renal failure patients are missing. Separate or additive effects of vitamin B6 and/or vitamin B12 on the homocysteine concentration in patients with renal failure have not been observed so far. Further research is needed to identify the optimal therapeutic dose and/or combination of vitamins in the therapy of hyperhomocysteinemia due to renal insufficiency.

Human Homocysteine Catabolism: Three Major Pathways and Their Relevance to Development of Arterial Occlusive Disease

Two separate metabolic pathways that methylate homocysteine to methionine are known in humans, utilizing, respectively, 5-methyltetrahydrofolate and betaine as methyl donors. Deficiency of the folate-dependent methylation system is linked to hyperhomocysteinemia. Our data suggest that this deficiency leads to concurrent metabolic down-regulation of homocysteine transsulfuration that may contribute to hyperhomocysteinemia. By contrast, no instances have been reported of hyperhomocysteinemia resulting from deficiencies of betaine-dependent homocysteine methylation. Long-term betaine supplementation of 10 patients, who had pyridoxine-resistant homocystinuria and gross hyperhomocysteinemia due to deficiency of cystathionine β-synthase activity, caused a substantial lowering of plasma homocysteine, which has now been maintained for periods of up to 13 years. Betaine had to be taken regularly because the effect soon disappeared when treatment was stopped. In conclusion, depressed activity of the transsulfuration pathway may contribute to hyperhomocysteinemia because of primary deficiencies of enzymes of either the transsulfuration or of the folate-dependent methylation pathways. Stimulation of betaine-dependent homocysteine remethylation causes a commensurate decrease in plasma homocysteine that can be maintained as long as betaine is taken.

Hyperhomocysteinaemia: a role in the accelerated atherogenesis of chronic renal failure?

Moderate hyperhomocysteinaemia has recently been established as an independent risk factor for atherothrombotic disease. It might be caused by heterozygosity for cystathionine beta-synthase deficiency, an enzyme involved in the conversion of methionine to cysteine through the transsulphuration pathway or by inherited thermolability of the enzyme which remethylates homocysteine into methionine. In chronic renal failure (CRF) homocysteine levels are significantly elevated at a relatively early stage. The normal kidney possibly plays an important role in homocysteine catabolism, which cannot be performed in CRF. Alternatively, decreased extrarenal catabolism can contribute to the hyperhomocysteinaemia in this disease state. Treatment with folic acid, 5 mg daily, significantly lowers homocysteine levels in chronic renal patients.

Are neuropsychiatric manifestations of folate, cobalamin and pyridoxine deficiency mediated through imbalances in excitatory sulfur amino acids?

Folate, cobalamin and pyridoxine deficiency are associated with psychiatric or neurological symptomatology. Disturbances in sulfur amino acid metabolism leading to accumulation of homocysteine occurs in all three conditions as the metabolism of homocysteine depends on enzymes requiring these vitamins as cofactors. Oxidation products of homocysteine (homocysteine sulfinic acid and homocysteic acid) and cysteine (cysteine sulfinic acid and cysteic acid) are excitatory sulfur amino acids and may act as excitatory neurotransmitters, whereas taurine and hypotaurine (decarboxylation products of cysteic acid and cysteine sulfinic acid) may act as inhibitory transmitters. Homocysteic acid and cysteine sulfinic acid have been considered as endogenous ligands for the N-methyl-D-aspartate (NMDA) type of glutamate receptors. The profile of these sulfur amino acid neurotransmitters could be altered in a similar fashion in states of decreased availability of folate, cobalamin or pyridoxine. It is proposed that the mechanism of neuropsychiatric manifestations in all three conditions result from a combination of two insults to homocysteine catabolism in the brain.

Vitamin B−6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats

The plasma homocysteine response to methionine loading was assessed in vitamin B-6- and folate-deficient rats. Rats fed vitamin B-6- or folate-deficient diets for 4 wk were administered a gastric gavage of methionine (100 mg/kg body wt). Subsequent plasma analyses revealed a peak post-methionine load increase in plasma homocysteine concentration of > 300 mumol/L in the vitamin B-6-deficient rats. Folate-deficient rats exhibited no significant changes in plasma homocysteine after the load. These disparate responses can be explained by the observed increase in hepatic S-adenosylmethionine (SAM) concentration because of the load. In vitamin B-6 deficiency, increased SAM inhibits homocysteine remethylation, which, in conjunction with the impaired homocysteine catabolism due to the deficiency and the increased synthesis of homocysteine due to the methionine load, leads to a large elevation of homocysteine in the blood. In folate deficiency, increased SAM activates homocysteine catabolism, which compensates for the increased synthesis of homocysteine due to the load and thus no change in blood homocysteine is observed. These results have significant bearing on the interpretation of both positive and negative responses to methionine loading in humans.

Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism.

In a recent hypothesis [Selhub and Miller (1992) Am. J. Clin. Nutr. 55, 131-138], we proposed that homocysteinaemia arises from an interruption in S-adenosylmethionine's (AdoMet) coordinate regulation of homocysteine metabolism. The present study was undertaken to test a prediction of this hypothesis, that homocysteinaemia due to folate deficiency results from impaired homocysteine remethylation due to the deficiency and impaired synthesis of AdoMet, with the consequent inability of this metabolite to function as an activator of homocysteine catabolism through cystathionine synthesis. Rats were made folate-deficient by feeding them with a folate-free amino-acid-defined diet supplemented with succinylsulphathiazole. After 4 weeks, the deficient rats exhibited a 9.8-fold higher mean plasma homocysteine concentration and a 3.2-fold lower mean hepatic AdoMet concentration compared with folate-replete controls. Subsequent supplementation for 3 weeks of the folate-deficient rats with increasing levels of folate in the diet resulted in graded decreases in plasma homocysteine levels, accompanied by graded increases in hepatic AdoMet levels. Thus plasma homocysteine and hepatic AdoMet concentrations were inversely correlated as folate status was modified. In a second experiment, the elevation of plasma homocysteine in the deficient rats was found to be reversible within 3 days by intraperitoneal injections of ethionine. This effect of ethionine is thought to be exerted through S-adenosylethionine, which is formed in the liver of these rats. Like AdoMet, S-adenosylethionine is an activator of cystathionine beta-synthase and will effectively promote the catabolism of homocysteine through cystathionine synthesis. In crude liver homogenates of the rats treated with ethionine, cystathionine beta-synthase activity was 3-fold higher than that measured in homogenates from vehicle-treated controls.