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Biomedical subjects

J Selhub

Publications and source records attributed to J Selhub.

At least 91 records · Page 5Linked to original sources
PubMed1997

Abnormal homocysteine metabolism in rheumatoid arthritis.

OBJECTIVE: To assess total homocysteine (tHcy) metabolism in patients with rheumatoid arthritis (RA). METHODS: Assessments were performed to determine the fasting levels of tHcy and the increase in tHcy in response to methionine (Met) challenge in blood samples from 28 patients with RA and 20 healthy age-matched control subjects. RESULTS: Fasting levels of tHcy were 33% higher in the RA patients than in the control subjects (mean +/- SD 11.7 +/- 1.5 nmoles/ml versus 8.8 +/- 1.1 nmoles/ml; P < 0.01). Four hours after Met challenge, the increase in plasma tHcy levels (delta tHcy) was higher in the RA patients (20.9 +/- 10.4 nmoles/ml) than in the control subjects (15.5 +/- 1.6 nmoles/ml) (P < 0.02). In a subgroup analysis, the delta tHcy in patients taking methotrexate (12.9 +/- 2.2 nmoles/ml) did not differ from that in the control group, while the delta tHcy in patients not taking methotrexate (25.3 +/- 1.7 nmoles/ml) was significantly higher (P < 0.0001). CONCLUSION: Elevated tHcy levels occur commonly in patients with RA, and may explain some of the increased cardiovascular mortality seen in such patients. Studies of the prevalence and mechanism of hyperhomocysteinemia in RA are warranted.

Adult↗
PubMed1997

Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene.

Folate is essential for the de novo biosynthesis of purines and thymidylate, and is an important mediator in the transfer of methyl groups for DNA methylation. Folate deficiency, therefore, could contribute to abnormal DNA integrity and methylation patterns. We investigated the effect of isolated folate deficiency in rats on DNA methylation and DNA strand breaks both at the genomic level and within specific sequences of the p53 tumor suppressor gene. Our data indicate that folate deficiency induces DNA strand breaks and hypomethylation within the p53 gene. Such alterations either did not occur or were chronologically delayed when examined on a genome-wide basis, indicating some selectivity for the exons examined within the p53 gene. Folate insufficiency has been implicated in the development of several human and experimental cancers, and aberrations within these regions of the p53 gene that were examined in this study are thought to play an integral role in carcinogenesis. The aforementioned molecular alterations may therefore be a means by which dietary folate deficiency enhances carcinogenesis.

Animals↗
PubMed1997

Effect of L-Dopa and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats.

L-Dopa is the most effective drug known for the treatment of Parkinson's disease. However, the large doses required to treat this neurodegenerative disorder can significantly affect tissue concentrations of sulfur amino acid metabolites due to peripheral and central O-methylation. These effects include decreases in tissue concentrations of the biochemical methyl donor S-adenosylmethionine (SAM), increases in tissue concentrations of the methylation inhibitor S-adenosylhomocysteine (SAH), and increases in plasma concentrations of homocysteine, recently identified as an independent risk factor for vascular disease. In the present study, the ability of the catechol-O-methyltransferase inhibitor Ro 41-0960 to prevent L-Dopa-induced changes in SAM, SAH, and homocysteine concentrations was determined in rats. Rats were injected intraperitoneally with Ro 41-0960 or vehicle 30 min prior to an intraperitoneal injection of L-Dopa or vehicle. One hour after the second injection, the rats were killed and their brains, livers, spleens, kidneys, and plasma collected. SAM and SAH concentrations were then determined in discrete brain regions and peripheral tissues, and total homocysteine concentrations were determined in plasma. In the rats treated with only L-Dopa, decreased SAM concentrations and increased SAH concentrations were found in all brain regions and peripheral tissues measured, and increased homocysteine concentrations were found in plasma, consistent with previous reports. In rats pretreated with Ro 41-0960, however, these L-Dopa-induced effects on sulfur amino acid metabolite concentrations were attenuated or prevented entirely. It remains to be determined if this sparing effect of Ro 41-0960 on sulfur amino acid metabolites has clinical significance.

Animals↗
PubMed1997

Excess prevalence of fasting and postmethionine-loading hyperhomocysteinemia in stable renal transplant recipients.

Hyperhomocysteinemia, either fasting or after methionine loading, may contribute to the increased incidence of cardiovascular disease events experienced by renal transplant recipients. Limited data are available on fasting homocysteine (Hcy) levels, and none on postmethionine-loading Hcy levels, in these patients. We assessed the prevalence and potential determinants of fasting and postmethionine-loading hyperhomocysteinemia in 29 stable renal transplant recipients and 58 age- and sex-matched, population-based controls free of renal disease with serum creatinine levels of 1.5 mg/dL or less. Total (t) plasma Hcy was determined fasting and 2 hours after methionine loading, along with fasting determinations of the B-vitamin cofactors/substrates for Hcy metabolism, ie, pyridoxal 5'-phosphate, B-12, and folate and serum creatinine. Geometric mean fasting (18.1 versus 9.8 microM, P < .001) and postmethionine-loading increase (22.0 versus 15.2, P = .001) in tHcy levels were significantly greater in the renal transplant recipients, as were the prevalence odds (with 95% confidence intervals) for fasting [14.8 (3.4-64.7)], postmethionine loading [6.9 (1.5-32.8)], combined fasting and postmethionine-loading [18.0 (2.3-142.1)] hyperhomocysteinemia, and inadequate circulating folate [4.2 (1.1-16.5)] or pyridoxal 5'-phosphate [3.2 (0.9-11.0) status. Correlation analyses suggested important potential relationships between creatinine and both fasting (+0.64, P < .001) and postmethionine-load increase (+0.38, P = .045) in tHcy, folate and fasting (-0.41, P = .025) tHcy, and pyridoxal 5'-phosphate and postmethionine-loading increase (-0.33, P = .091) in tHcy. We conclude that there is an excess prevalence of fasting and postmethionine-loading hyperhomocysteinemia in stable renal transplant recipients. Renal function is related to both fasting and postmethionine loading-hyperhomocysteinemia, inadequate folate status is associated with fasting hyperhomocysteinemia, and inadequate vitamin B-6 status may be related to postmethionine-loading hyperhomocysteinemia in this patient population.

Adult↗
PubMed1997

Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study.

There is an excess prevalence of hyperhomocysteinemia in dialysis-dependent end-stage renal disease (ESRD) patients. Cross-sectional studies of the relationship between elevated total homocysteine (tHcy) levels and prevalent cardiovascular disease (CVD) in this patient population suffer from severe methodologic limitations. No prospective investigations examining the association between tHcy levels and the subsequent development of arteriosclerotic CVD outcomes among maintenance dialysis patients have been reported. To assess whether elevated plasma tHcy is an independent risk factor for incident CVD in dialysis-dependent ESRD patients, we studied 73 maintenance peritoneal dialysis or hemodialysis patients who received a baseline examination between March and December 1994, with follow-up through April 1, 1996. We determined the incidence of nonfatal and fatal CVD events, which included all validated coronary heart disease, cerebrovascular disease, and abdominal aortic/lower-extremity arterial disease outcomes. After a median follow-up of 17.0 months, 16 individuals experienced at least one arteriosclerotic CVD event. Cox proportional-hazards regression analyses, unadjusted and individually adjusted for creatinine, albumin, and total cholesterol levels, total/HDL cholesterol ratio, dialysis adequacy/residual renal function, baseline CVD, and the established CVD risk factors (ie, age, sex, smoking, hypertension, diabetes/glucose intolerance, and dyslipidemia) revealed that tHcy levels in the upper quartile (> or = 27.0 mumol/L) versus the lower three quartiles (< 27.0 mumol/L) were associated with relative risk estimates (hazards ratios, with 95% confidence intervals for the occurrence of (pooled) nonfatal and fatal CVD ranging from 3.0 to 4.4; 95% confidence intervals (1.1-8.1) to (1.6-12.2). We conclude that the markedly elevated fasting tHcy levels found in dialysis-dependent ESRD patients may contribute independently to their excess incidence of fatal and nonfatal CVD outcomes.

Adult↗
PubMed1997

Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease.

Mild hyperhomocysteinemia, a risk factor for occlusive arterial disease, can be caused by disruptions of homocysteine metabolism. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, the methyl donor for homocysteine remethylation to methionine. A common mutation in MTHFR, an alanine-to-valine substitution, may contribute to mild hyperhomocysteinemia in coronary artery disease (CAD). To test this hypothesis, we studied 152 patients with CAD by mutation analysis, MTHFR enzymatic assays, and measurements of plasma homocysteine and several vitamins. The MTHFR mutation was associated with reduced enzymatic activity and increased enzyme thermo-lability in these patients. The difference in the prevalence of the homozygous mutant genotype between the CAD patients (14%) and an unmatched group of healthy subjects (10%) was not significant. However, individuals with the homozygous mutant genotype had higher plasma homocysteine, particularly when plasma folate was below the median value. This genetic-environmental interaction is proposed to be a risk factor for CAD.

Adult↗
PubMed1997

Hyperhomocysteinemia and thrombosis: acquired conditions.

Hyperhomocysteinemia is a condition which, in the absence of kidney disease, indicates a disrupted sulfur amino acid metabolism, either because of vitamin (folate, B12 and B6) deficiency or a genetic defect. Epidemiological evidence suggests that mild hyperhomocysteinemia is associated with increased risk of arteriosclerotic disease and stroke. The relationship between hyperhomocysteinemia and thrombosis has been investigated in 10 studies involving a total of 1200 patients and 1200 controls. Eight of these studies demonstrated positive association with odds ratios that ranged from 2 to 13. This association was enhanced by including a methionine loading test. There is some evidence which suggests that hyperhomocysteinemia and APC resistance have a synergistic effect on the onset of thrombotic disease. Studies on the mechanism that underlies the relationship between thrombosis and hyperhomocysteinemia used non-physiologically high levels of homocysteine, rendering the data doubtful as to their patho-physiological relevance.

Clinical Trials as Topic↗
PubMed1996

Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid.

The biological basis or mechanism whereby folate supplementation protects against heart and neural tube defect is unknown. It has been hypothesized that the amino acid homocysteine may be the teratogenic agent, since serum homocysteine increases in folate depletion; however, this hypothesis has not been tested. In this study, avian embryos were treated directly with D,L-homocysteine or with L-homocysteine thiolactone, and a dose response was established. Of embryos treated with 50 microliters of the teratogenic dose (200 mM D,L-homocysteine or 100 mM L-homocysteine thiolactone) on incubation days 0, 1, and 2 and harvested at 53 h (stage 14), 27% showed neural tube defects. To determine the effect of the teratogenic dose on the process of heart septation, embryos were treated during incubation days 2, 3, and 4; then they were harvested at day 9 following the completion of septation. Of surviving embryos, 23% showed ventricular septal defects, and 11% showed neural tube defects. A high percentage of the day 9 embryos also showed a ventral closure defect. The teratogenic dose was shown to raise serum homocysteine to over 150 nmol/ml, compared with a normal level of about 10 nmol/ml. Folate supplementation kept the rise in serum homocysteine to approximately 45 nmol/ml, and prevented the teratogenic effect. These results support the hypothesis that homocysteine per se causes dysmorphogenesis of the heart and neural tube, as well as of the ventral wall.

Animals↗
PubMed1996

Folic acid fortification of the food supply. Potential benefits and risks for the elderly population.

OBJECTIVE: To estimate the potential benefits and risks of food folic acid fortification for an elderly population. Benefits are expected through the improvement of folate and homocysteine status, but there is also a risk of masking or precipitating clinical manifestations related to vitamin B12 deficiency with increasing exposure to folic acid. DESIGN: Cross-sectional analysis, with projected change at various levels of folic acid fortification. SETTING: Participants in the Framingham Heart Study original cohort. PARTICIPANTS: A total of 747 subjects aged 67 to 96 years who both completed usable food frequency questionnaires and had blood concentrations of B vitamins and homocysteine measured. MAIN OUTCOME MEASURES: Projected blood folate and homocysteine concentrations and combined high folate intake and low plasma vitamin B12 concentration. RESULTS: Percentages of this elderly population with folate intake below 400 microg/d are projected to drop from 66% at baseline to 49% with 140 microg of folate per 100 g of cereal-grain product, to 32% with 280 microg, to 26% with 350 microg, and to 11% with 700 microg. Percentages with elevated homocysteine concentrations (>14 micromol/L) are projected to drop from 26% at baseline to 21% with 140 microg of folate per 100 g, to 17% with 280 microg, to 16% with 350 microg, and to 12% with 700 microg. Without fortification, the prevalence of combined high folate intake (>1000 microg/d) and low plasma vitamin B12 concentration (<185 pmol/L [<250 pg/mL]) was 0.1%. This is projected to increase to 0.4% with folate fortification levels of 140 to 350 microg/100 g and to 3.4% with 700 microg. CONCLUSION: The evidence suggests that, at the level of 140 microg/100 g of cereal-grain product mandated by the Food and Drug Administration, the benefits of folate fortification, through projected decreases in homocysteine level and heart disease risk, greatly outweigh the expected risks. However, quantification of the actual risks associated with vitamin B12 deficiency remains elusive. Before higher levels of folic acid fortification are implemented, further research is needed to better understand the clinical course of various forms of vitamin B12 deficiency, to measure the potential effect of high folate intake on this course, and to identify cost-effective approaches to the identification and treatment of all forms of vitamin B12 deficiency.

Aged↗
PubMed1996

Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.

BACKGROUND: A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure. We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease. METHODS AND RESULTS: Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3 +/- 14.8 years). Folate, vitamin B12, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6 +/- 1.5 versus 10.1 +/- 1.7 mumol/L; P < .01). Abnormally high concentrations (> 95th percentile for control subjects, 16.3 mumol/L) were seen in 149 patients (85%) with end-stage renal disease (P < .001). Patients with a homocysteine concentration in the upper two quintiles (> 27.8 mumol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P = .007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B6 deficiency was more frequent in patients than in the normal reference population (18% versus 2%; P < .01). CONCLUSIONS: A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.

Aged↗
PubMed1996

Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians.

BACKGROUND: Hyperhomocysteinemia appears to be an independent risk factor for coronary disease. Elevated levels of plasma total homocysteine (tHCY) can result from genetic or nutrient-related disturbances in the transsulfuration or remethylation pathways for homocysteine metabolism. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate, which serves as a methyl donor for remethylation of homocysteine to methionine. A common mutation in MTHFR recently has been identified. METHODS AND RESULTS: We assessed the polymorphism in MTHFR, plasma tHCY, and folate using baseline blood levels among 293 Physicians' Health Study participants who developed myocardial infarction (MI) during up to 8 years of follow-up and 290 control subjects. The frequency of the three genotypes was (-/-) (homozygous normal), 47%; (+/-) (heterozygous), 41%; and (+/+) (homozygous mutant), 12%, with a similar distribution among both MI case patients and control subjects. Compared with those with genotype (-/-), the relative risk (RR) of MI among those with (+/-) was 1.1 (95% CI, 0.8 to 1.5), and it was 0.8 (0.5 to 1.4) for the (+/+) genotype; none of these RRs were statistically significant. However, those with genotype (+/+) had an increased mean tHCY level (mean +/- SEM, 12.6 +/- 0.5 nmol/ mL), compared with those with genotype (-/-) (10.6 +/- 0.3) (P < .01). This difference was most marked among men with low folate levels (the lowest quartile distribution of the control subjects): those with genotype (+/+) had tHCY levels of 16.0 +/- 1.1 nmol/mL, compared with 12.3 +/- 0.6 nmol/mL (P < .001) for genotype (-/-). CONCLUSIONS: In this population, MTHFR polymorphism was associated with higher homocysteine levels but not with risk of MI. A gene-environment interaction might increase the risk by elevating tHCY, especially when folate intake is low.

Adult↗
PubMed1996

Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus.

BACKGROUND: The aim of this study was to assess whether plasma homocysteine is a risk factor for stroke and other thrombotic events in patients with systemic lupus erythematosus (SLE)--a condition known to be associated with premature atherothrombotic complications. METHODS: In this prospective study, we investigated the association between homocysteine and risk of stroke and thrombotic events in 337 SLE patients in the Hopkins Lupus Cohort Study, with follow-up of 1619 person-years (mean 4.8 [SD 1.7] years). Each patient had four follow-up assessments per year to obtain information about established risk factors for thrombosis and coronary artery disease. The prospectively defined endpoints were occurrence of stroke and arterial or venous thrombotic events between 1987 and 1995. Blood samples were taken at study entry from fasting patients. Plasma homocysteine, folate, vitamin B12, and pyridoxal 5'-phosphate (PLP) concentrations were measured. Raised homocysteine concentrations were defined as more than 14.1 mumol/L. FINDINGS: 93% of the study population were women, 54% African American, and 45% white. The mean age of participants was 34.9 (SD 11.7) years. During follow-up there were 29 cases of stroke and 31 arterial thrombotic events. Raised homocysteine concentrations were found in 51 (15%) SLE patients. The log-transformed total homocysteine concentrations correlated with serum folate (r = 0.31, p = 0.0001). In univariate analyses, raised homocysteine concentrations were significantly associated with stroke (odds ratio 2.24 [95% CI 1.22-4.13], p = 0.01) and arterial thrombotic events (3.74 [1.96-7.13], p = 0.0001). After adjustment for established risk factors, total plasma homocysteine concentrations remained an independent risk factor for stroke (2.44 [1.04-5.75], p = 0.04) and arterial thromboses (3.49 [0.97-12.54], p = 0.05). INTERPRETATION: Homocysteine is a potentially modifiable, independent risk factor for stroke and thrombotic events in patients with SLE.

Adult↗
PubMed1996

Hyperhomocysteinemia, hyperfibrinogenemia, and lipoprotein (a) excess in maintenance dialysis patients: a matched case-control study.

Maintenance dialysis patients experience an exceedingly high incidence of arteriosclerotic cardiovascular disease (CVD) events that are poorly predicted by traditional CVD risk factor indices. We evaluated the prevalence of three non-traditional CVD risk factors, i.e. hyperhomocysteinemia, hyperfibrinogenemia, and lipoprotein (a) Lp(a)) excess, and combined hyperhomocysteinemia, hyperfibrinogenemia, and Lp(a) excess, in maintenance dialysis patients. Fasting total plasma homocysteine (Hcy), fibrinogen, Lp(a), glucose, and total and HDL cholesterol levels, and traditional CVD risk factor (i.e. glucose tolerance, smoking, hypertension, dyslipidemia) prevalences were assessed in 71 dialysis patients and 71 age, sex, and race matched Framingham Study controls free of clinical renal disease, with normal serum creatinine (< or = 1.5 mg/dl). Mean plasma Hcy 23.7 vs. 9.9 microM, P = 0.0001), fibrinogen (457 vs. 309 mg/dl, P = 0.0001), and Lp(a) (30 vs. 17 mg/dl, P = 0.0070) levels were substantially increased in the dialysis patients. Matched odds ratios (with 95% confidence intervals), dialysis patients/controls, for hyperhomocysteinemia, hyperfibrinogenemia, and Lp(a) excess, alone or combined, were markedly greater in the dialysis patients, with no evidence of confounding by the traditional CVD risk factors: hyperhomocysteinemia, 105.0 (29.9-368.9); hyperfibrinogenemia, 16.6 (6.6-42.0); Lp(a) excess, 3.5 (1.5-8.4); all three combined 35.0 (5.7-199.8). Given in vitro evidence that Hcy, Lp(a), and fibrinogen interact to promote atherothrombosis, combined hyperhomocysteinemia, hyperfibrinogenemia, and Lp(a) excess may contribute to the high incidence of vascular disease sequelae experienced by dialysis patients, which is inadequately explained by traditional CVD risk factors. Controlled, prospective studies of well-characterized maintenance dialysis cohorts are urgently required to substantiate this hypothesis.

Adult↗
PubMed1996

Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. METHODS AND RESULTS: To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations ( < 15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater (P<.05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels > or = 15.4 nmol/L. CONCLUSIONS: Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.

Adult↗
PubMed1996

Lack of effect of oral N-acetylcysteine on the acute dialysis-related lowering of total plasma homocysteine in hemodialysis patients.

Hyperhomocysteinemia refractory to standard B-vitamin supplementation treatment persists in > or = 75% of maintenance dialysis patients, potentially increasing their risk for atherothrombotic sequelae. We examined whether predialysis administration of oral N-acetylcysteine (NAC), which acutely increases the non-protein bound, dialyzable fraction of plasma homocysteine, might augment the homocysteine-lowering effect of dialysis therapy. Predialysis and postdialysis total plasma homocysteine levels were determined on a control day, and on a day in which oral NAC (1200 mg) was administered predialysis in n = 11 maintenance hemodialysis patients. Although NAC treatment had no significant effect on hemodialysis removal of plasma homocysteine (P = 0.594), we observed a 16% reduction (P = 0.033) in non-fasting prehemodialysis total plasma homocysteine on the NAC treatment vs. non-treatment day. Longer term, placebo-controlled confirmation of this finding will be required to evaluate the possible chronic homocysteine-lowering efficacy of NAC treatment in hemodialysis patients.

Acetylcysteine↗
PubMed1996

Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients.

Limited data are available on the determinants of homocysteinemia or the association between plasma homocysteine (Hcy) levels and prevalent cardiovascular disease (CVD) in maintenance dialysis patients. We assessed etiology of renal failure, residual renal function and dialysis adequacy-related variables, and vitamin status, as determinants of fasting total plasma homocysteine (Hcy) in 75 maintenance dialysis patients. We also assessed the potential interactive effect on plasma Hcy of folate status and a common mutation (ala to val; homozygous val-val frequency approximately 10%) in methylenetetrahydrofolate reductase (MTHFR), a folate-dependent enzyme crucial for the remethylation of homocysteine (Hcy) to methionine. Lastly, we evaluated whether the Hcy levels differed amongst these patients in the presence or absence of prevalent CVD, after adjustment for the traditional CVD risk factors. Fasting total plasma Hcy, folate, pyridoxal 5'-phosphate (PLP; active B6), B12, creatinine, glucose, total and HDL cholesterol levels, and presence of the ala to val MTHFR mutation were determined, and clinical CVD and CVD risk factor prevalence were ascertained. General linear modelling/analysis of covariance revealed: (1) folate status and serum creatinine were the only significant independent predictors of fasting Hcy; (2) there was a significant interaction between presence of the val mutation and folate status, i.e., among patients with plasma folate below the median (< 29.2 ng/ml), geometric mean Hcy levels were 33% greater (29.0 vs. 21.8 microM, P = 0.012) in the pooled homozygotes (val-val) and heterozygotes (ala-val) for the ala to val mutation, vs. normals (ala-ala); (3) there was no association between prevalent CVD and plasma Hcy. Given potentially intractable survivorship effects, prospective cohort studies will be required to clarify the relationship between plasma Hcy or any putative CVD risk factor, and incident CVD in dialysis patients. If a positive association between plasma Hcy and incident CVD can be established in maintenance dialysis patients, the current data provide a rationale for additional folic acid supplementation in this patient population.

Adult↗
PubMed1996

Oxidative damage caused by free radicals produced during catecholamine autoxidation: protective effects of O-methylation and melatonin.

Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss of dopaminergic neurons in the nigrostriatal region of the brain that occurs during normal aging and in Parkinson's disease. In the present study, the potential protective effects of catecholamine O-methylation and of melatonin against catecholamine autoxidation-induced protein damage were assessed in vitro using the oxygen radical absorbance capacity (ORAC) assay. The rate of oxidation of the fluorescent protein porphyridium cruentum beta-phycoerythrin (beta-PE) caused by the oxidizing agent CuSO4 was shown to be accelerated by addition of the catecholamines dopamine and L-dopa. Replacement of dopamine and L-dopa in the assay with their O-methylated metabolites 3-O-methyldopamine and 3-O-methyldopa significantly decreased the rate of beta-PE oxidation. When melatonin was added to the ORAC assay in combination with dopamine or L-dopa, the rate of beta-PE oxidation was decreased as well. These findings were consistent with the following interpretations: (1) O-methylated catecholamines are less susceptible to autoxidation than their nonmethylated precursors, and (2) melatonin, which has recently been shown to be a powerful antioxidant, is capable of scavenging free radicals produced during catecholamine autoxidation. These findings suggest that O-methylation and melatonin may be important components of the brain's antioxidant defenses against catecholamine autoxidation and may protect against consequent dopaminergic neurodegeneration.

Catecholamines↗