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PubMed2004

New cardiovascular risk factors: homocysteine and vitamins involved in homocysteine metabolism.

Among various cardiovascular risk factors, hyperhomocysteinemia has recently emerged as an important one. While there are currently no doubts on the relationship between severe hyperhomocysteinemia and vascular disease, some uncertainty still persists on the relationship between mild hyperhomocysteinemia and vascular disease. Several group B vitamins, namely vitamin B6, vitamin B12, and folate, influence homocysteine metabolism, being cofactors of the main metabolic pathways which allow the disposal of this amino acid. There are also, however, suggestions from the literature that group B vitamins, and in particular vitamin B6 (pyridoxine/pyridoxal-phosphate), are modulators of cardiovascular risk independent of homocysteine. The results of a recent study of ours, with a long follow-up, indeed suggest that homocysteine and vitamin B6 are independent and additive cardiovascular risk factors.

Biomarkers↗
PubMed2002

[Correlation analysis between plasma homocysteine level and polymorphism of homocysteine metabolism related enzymes in ischemic cerebrovascular or cardiovascular diseases].

OBJECTIVE: To investigate the changes of plasma homocysteine (Hcy) level in patients with ischemic cerebrovascular or cardiovascular disease and analyze the relationship between plasma Hcy levels and the mutations in Hcy metabolism related enzymes, including methylene tetrahydrofolate reductase (MTHFR) C677T, cystathionine beta-synthetase (CBS) 844ins68 and methionine synthetase (MS) A2756G. METHODS: By using the HPLC-FLD method, the plasma total homocysteine (tHcy) concentration was determined in 86 patients with cerebral infarction, 66 with myocardial infarction and 80 healthy controls. The association of plasma tHcy levels with cardiovascular or cerebrovascular disease and mutations of MTHFR C677T, CBS 844 ins 68 and MS A2756G were evaluated by statistic methods. RESULTS: In the patient groups, the plasma tHcy concentrations increased significantly as compared with healthy controls. The individuals homozygous for MTHFR C677T mutation had significantly higher plasma Hcy levels. CONCLUSION: Hyperhomocysteinemia is an important risk factor for ischemic cerebrovascular and cardiovascular disease. The homozygosity of MTHFR C677T may contribute to the increase of plasma Hcy and vascular damage.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2006

Plasma total homocysteine level and bone mineral density: the Hordaland Homocysteine Study.

BACKGROUND: Plasma total homocysteine (tHcy) has been associated with hip fracture but not directly with bone mineral density (BMD). We examined the association of hip BMD with levels of plasma tHcy, folate, and vitamin B12 and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C polymorphisms. METHODS: Bone mineral density was measured between 1997 and 2000 in 2268 men and 3070 women, aged 47 to 50 and 71 to 75 years, from the Hordaland Homocysteine Study cohort. Low BMD was defined as BMD in the lowest quintile for each sex and age group. Linear, logistic, and generalized additive regression models were used. RESULTS: Plasma levels of tHcy were inversely related to BMD among middle-aged and elderly women (P<.001) but not among men. The multiple adjusted odds ratio for low BMD among subjects with high (>or=15 micromol/L [>or=2.02 mg/L]) compared with low (<9 micromol/L [<1.22 mg/L]) tHcy level was 1.96 (95% confidence interval, 1.40-2.75) for women and was not significant for men. Additional adjustments for plasma folate level or intake of calcium and vitamin D did not substantially alter the results. Plasma folate level was associated with BMD in women only. We observed no association between BMD and vitamin B12 level or the MTHFR polymorphisms. CONCLUSIONS: Elevated tHcy and low folate levels were associated with reduced BMD in women but not in men. These findings suggest that tHcy may be a potential modifiable risk factor for osteoporosis in women.

Age Distribution↗
PubMed2006

Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson's disease patients.

BACKGROUND: Elevated plasma total homocysteine (tHcy) appeared in levodopa/dopadecarcoxylase inhibitor (DDI) treated patients with Parkinson's disease (PD). One therapeutic approach for tHcy reduction is vitamine supplementation, since folic acid and cobalamine catalyse and enhance metabolism of tHcy to methionine. A further therapeutic alternative is inhibition of catechol-O-methyltransfrase (COMT) on a regular basis, when levodopa/DDI treatment is performed. METHODS: We measured the concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), tHcy, levodopa and 3-O-methyldopa in plasma of 13 levodopa treated PD patients before first drug intake at 0600 hours. Blood samples were taken before and after 2 days of additional application of the centrally acting catechol-O-methyltransferase inhibitor tolcapone 100 mg t.i.d. RESULTS: Plasma levels of SAH [day 1: 48.32+/-22.52, 23.92-98.25 (mean+/-SD, range; micromol/l); day 3: 37.72+/-15.84, 23.4-61.89; p = 0.01] and tHcy (day 1: 13.88+/-5.62, 7.63-24.81; day 3: 11.38+/-4.44, 5.98-20.45; p = 0.04) significantly reduced. Plasma levels of levodopa did not significantly (p = 0.17) increase, whereas 3-OMD concentrations significantly (p = 0.0002) reduced after additional tolcapone intake. There was no significant change of SAM plasma levels (p = 0.22). CONCLUSION: Our prospective trial shows, that COMT inhibition with tolcapone lowers tHcy synthesis. Tolcapone may also possess beside its proven, occasional, hepatotoxic potency also beneficial effects via decrease of SAH and tHcy. This may hypothetically reduce homocysteine mediated progress of neuronal degeneration and the risk for onset of dementia, vascular disease and polyneuropathy in levodopa treated PD patients in the long term.

Aged↗
PubMed1995

Oral administration of homocysteine leads to increased plasma triglycerides and homocysteic acid-additional mechanisms in homocysteine induced endothelial damage?

Increased plasma homocyst(e)ine is strongly correlated with occlusive arterial diseases. A series of different hypotheses have been reported including involvement of free oxygen radicals and therefore oxidative stress. We determined plasma homocyst(e)ine and homocysteic acid levels after oral low dose homocysteine thiolactone administration to rats for a period of six weeks. Plasma levels of homocyst(e)ine and triglycerides were significantly elevated in the group fed homocysteine thiolactone. GC/MS determination of ketone body formation showed that the underlying mechanism for the increase of triglycerides seems to be inhibition of fatty acid oxidation. Homocysteic acid was detected in the experimental group exclusively. The present study showing a homocyst(e)ine correlated increase of plasma triglycerides by the inhibition of fatty acid oxidation may well propose an additional role of triglycerides for vascular pathology. The presence of homocysteic acid in the experimental group only would support the free oxygen radical hypothesis for the development of vascular changes but homocysteic acid as a potent neurotransmitter could play an independent role in the pathogenesis.

Administration, Oral↗
PubMed2002

Determination of homocysteine thiolactone and homocysteine in cell cultures using high-performance liquid chromatography with fluorescence detection.

A sensitive and simple method utilising fluorometric detection for the simultaneous routine monitoring of homocysteine thiolactone (HTL) and homocysteine (Hcy) in biological samples has been developed. Separation relies on isocratic ion-pairing and reversed-phase chromatography while the principle of the detection is that the lactone ring in HTL molecule is cleaved with an alkali to produce Hcy, which reacts with ortho-phthalaldehyde (OPA) in the absence of an added thiol reagent to form a stable fluorescent derivative. The method has a sensitivity of 200 fmol of HTL and 100 fmol for Hcy in the sample. The present method was applied to the determination of HTL and Hcy in Hep G2 cell.

Cell Culture Techniques↗
PubMed1998

Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study.

We report on the location and skewness of the distribution of plasma total homocysteine (tHcy) according to lifestyle indexes in 11,941 apparently healthy participants of the Hordaland Homocysteine Study. Most subjects were in two age groups: 9165 subjects were aged 40-42 y and 2351 subjects were aged 65-67 y. The remaining 425 subjects were of intermediate ages. In multivariate analysis, sex, age, folate intake, smoking status, and coffee consumption were the strongest determinants of tHcy concentration. The combined effect of the three modifiable factors was larger than the effect from each factor alone. A lifestyle profile characterized by low folate intakes, smoking, and coffee consumption was associated with a high median tHcy concentration and a pronounced skewness toward high tHcy values. In subjects characterized by a contrasting lifestyle profile [high folate intakes, nonsmoking status, and low coffee consumption (< 1 cup/d)], tHcy values were almost normally distributed and the median concentration was 3.0-4.8 micromol/L lower. Among all 40-42-y-old subjects, the 95% reference ranges based on geometric mean tHcy concentrations were 5.1-16.5 micromol/L for women and 6.2-18.7 micromol/L for men. The corresponding ranges for subjects characterized by high folate intakes, nonsmoking status, and low or moderate coffee consumption (< 5 cups/d) were 4.8-12.8 micromol/L and 6.2-14.7 micromol/L. These findings are relevant for establishing adequate reference ranges for tHcy and emphasize folate intake, smoking status, and coffee consumption as major acquired determinants of tHcy concentration in this general population.

Adult↗
PubMed2006

The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease.

The Hordaland Homocysteine Study (HHS) is a population-based study of more than 18,000 men and women in the county of Hordaland in Western Norway. The first investigation (HHS-I) took place in 1992-93, when the subjects were aged 40-67 y. In 1997-99, a follow-up study (HHS-II) of 7,053 subjects was carried out. In this large population, plasma levels of total homocysteine (tHcy) are associated with several physiologic and lifestyle factors and common diseases. Increasing age, male sex, smoking, coffee consumption, high blood pressure, unfavorable lipid profile, high creatinine, and the MTHFR 677C > T polymorphism are among the factors associated with increased tHcy levels; physical activity, moderate alcohol consumption, and a good folate or vitamin B-12 status are associated with lower tHcy levels. Subjects with raised tHcy levels have increased risk of cardiovascular morbidity, cardiovascular and noncardiovascular mortality, and are more likely to suffer from depression and from cognitive deficit (elderly). Among women, raised tHcy levels are associated with decreased bone mineral density and increased risk of osteoporosis. Women with raised tHcy levels also have an increased risk of having suffered from pregnancy complications and an adverse pregnancy outcome. Significant associations between tHcy and clinical outcomes are usually observed for tHcy levels > 15 micromol/L, but for most conditions, there is a continuous concentration-response relation with no apparent threshold concentration. Overall, the findings from HHS indicate that a raised tHcy level is associated with multiple clinical conditions, whereas a low tHcy level is associated with better physical and mental health.

Adult↗
PubMed1985

Phospholipid methylase activity, [3H]S-adenosyl-L-homocysteine binding, and S-adenosyl-L-methionine and S-adenosyl-L-homocysteine levels in rat brain during maturation.

The changes in activity of phospholipid methyltransferase I and [3H]S-adenosyl-L-homocysteine ([3H]SAH) binding were determined in cortical membrane preparations from newborn rats and rats 1, 2, and 8 months old. The activity of phospholipid methyltransferase I and the [3H]SAH binding were significantly greater (respectively, +30 and +40%) in newborn rats than in 1-, 2-, and 8-month-old rats. The methylated products at days 1 and 30 were identical. These changes in methyltransferase activity may be correlated with variations in concentration of S-adenosyl-L-methionine (SAM) and SAH. The endogenous SAM level was higher and the SAH level was lower in newborn compared with adult rats. These data suggested that the processes of methylation were favored in newborn rats. The modifications observed after treatment with L-homocysteine reinforced this hypothesis.

Animals↗
PubMed2003

Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid.

OBJECTIVE: The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. METHODS: We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (CSF) MMA and tHcy in 72 patients with MS and 23 controls. RESULTS: The mean plasma tHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12 levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age. CONCLUSIONS: The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.

Adult↗
PubMed2002

Interlaboratory variation of plasma total homocysteine measurements: results of three successive homocysteine proficiency testing surveys.

BACKGROUND: Numerous studies have demonstrated that increased plasma total homocysteine (tHcy), whether measured after fasting or after a methionine load, is associated with increased risk for cardiovascular and thromboembolic diseases. However, little information is available regarding interlaboratory variation of tHcy measurements, especially at the increased tHcy concentrations observed after loading. METHODS: We conducted three Homocysteine Proficiency Testing Surveys at 6-month intervals. Sets of five plasma pools with endogenous tHcy concentrations ranging from 5 to 48 micromol/L were sent to participants. We received 11, 23, and 17 responses in the first, second, and third surveys, respectively. The following methods were used by participating laboratories: fluorescence polarization immunoassay (FPIA); HPLC with fluorescent detection (HPLC-FD), further subdivided by type of reduction/derivatization; HPLC with electrochemical detection (HPLC-ED); amino acid analyzer with ninhydrin detection; and liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS). RESULTS: In surveys 1 and 2, no notable differences among the mean tHcy values obtained by the different methods performed were observed. In survey 3, tHcy values obtained by the FPIA method were significantly lower (P <0.05) at increased tHcy concentrations (34 micromol/L) compared with values obtained by HPLC-FD regardless of reduction/derivatization agents used. Our laboratory confirmed the observation that tHcy values obtained by the FPIA method differed from those obtained by HPLC-FD at increased tHcy concentrations by reanalyzing each pool 10 times by FPIA and HPLC-FD using tributylphosphine-ammonium 7-fluoro-2,1,3-benzoxadiazole-4-sulfonate (P <0.001 for tHcy >19 micro mol/L). The mean among-method variations in surveys 1, 2, and 3 were 19%, 12%, and 9.6%, respectively. When results of the three surveys were combined, the mean among-method variation on 170 samples was 13%. Within-method variation was lowest for the FPIA method (4.4%), and ranged from 11-20% for HPLC methods. CONCLUSIONS: Various degrees of imprecision and lack of correlation among tHcy methods indicate that there is a need to improve analytical precision, decrease analytical difference, and standardize tHcy measurements among laboratories.

Chromatography, High Pressure Liquid↗
PubMed2004

Serum total homocysteine levels and the prevalence of folic acid deficiency and C677T mutation at the MTHFR gene in an indigenous population of Amazonia: the relationship of homocysteine with other cardiovascular risk factors.

Hyperhomocysteinemia is a risk factor for cardiovascular disease. C677T mutation at the MTHFR gene and deficiencies of folic acid and vitamin B-12 may account for elevation of total homocysteine (tHcy). Ninety Brazilian Parkatêjê Indians (90.0% of the population without admixture, aged > or = 20 years) were studied. Hyperhomocysteinemia was observed in 26.7% of the Indians. No case of vitamin B-12 deficiency was detected. Folic acid deficiency was found in 43.3% of the subjects. Rates of mutated allele 677T and TT genotype were 40.7% and 14.0%, respectively. Prevalence of hypertension, dyslipidemia, smoking, WHR > or = 0.9, BMI > or = 25 kg/m2 and chronic alcohol use were 4.4%, 44.4%, 25.6%, 72.2%, 67.8%, and 0.0%, respectively. All creatinine values were normal. Natural logarithmic (ln) tHcy showed no correlation with age, but was positively correlated with systolic (r = 0.22) and diastolic (r = 0.21) blood pressure and triglycerides (r = 0.39) and inversely correlated with folic acid (r = -0.40) adjusted for age and sex. Total homocysteine (tHcy) was higher among TT genotype (P < .001). The multiple linear regression model, containing variables for sex, folic acid, TT genotype, and triglycerides, explained 50.0% of the variation of the ln tHcy. In summary, high rates of cardiovascular risk factors were discovered. C667T mutation and folic acid deficiency can explain, at least in part, the observed hyperhomocysteinemia.

Adult↗
PubMed2000

Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels.

A moderately elevated plasma total homocysteine (tHcy), whether measured during fasting or post-methionine load (PML), is increasingly being recognized as a risk factor for coronary artery diseases (CAD). However, etiologies for moderately elevated plasma tHcy, particularly with regard to the role of genetic influence on plasma tHcy levels, are still not well understood. In the current investigation, we studied 1025 individuals with respect to the effect of the 68-bp insertion (844ins68 variant) of the cystathionine beta-synthase (CBS) gene, the A(2756)G transition of the B(12)-dependent methionine synthase (MS) gene and the C(677)T transition of the methylenetetrahydrofolate reductase (MTHFR) gene on fasting and 4 h PML tHcy. Of these individuals, 153 (14.9%) were heterozygous for the 68-bp insertion, 329 (32.1%) were heterozygous for the G(2756) allele and 122 (11.9%) were homozygous for the C(677)T transition. Individuals heterozygous for the insertion had significantly lower PML increase in tHcy concentrations, while individuals homozygous for the A(2756)G transition had significantly lower fasting tHcy levels. A 2-way ANOVA showed that there was no interaction between the 844ins68 and the A(2756)G transition for either fasting tHcy or PML increase in tHcy, confirming the fact that the effect of these two genotypes on plasma tHcy levels are additive. The effects are opposite but additive with the C(677)50% of all individuals in this study carried polymorphic traits, which predisposed them to either higher or lower plasma tHcy concentrations, thus providing new evidence of the importance of genetic influences as determinants of tHcy levels.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2002

Plasma total homocysteine and hospitalizations for cardiovascular disease: the Hordaland Homocysteine Study.

BACKGROUND: Elevated total plasma homocysteine (tHcy) level is a risk factor for occlusive disease in the coronary, cerebral, and peripheral vessels and is related to several lifestyle factors associated with cardiovascular disease (CVD). OBJECTIVE: To examine the association of a single tHcy measurement on subsequent hospitalizations due to CVD. METHODS: A population-based prospective cohort study was conducted from April 1, 1992, to May 31, 1998 (mean follow-up, 5.3 years) in western Norway. The study included 17 361 individuals aged 40 to 42 or 65 to 67 years at baseline. Main outcome measure was CVD as the main hospital discharge diagnosis or coronary revascularization procedures (denoted "CVD hospitalizations") during follow-up (n = 1275). RESULTS: At baseline, participants with preexisting CVD had higher mean tHcy values than individuals without CVD. Risk of CVD hospitalizations increased significantly with increasing baseline tHcy only in the oldest age group. Here, multiple risk factor-adjusted hospitalization rate ratios in 5 tHcy categories (<9, 9-11.9, 12-14.9, 15-19.9, and >or=20 micromol/L [to convert tHcy to milligrams per liter, divide by 7.397]) were as follows: 1 (reference level), 1.00, 1.34, 1.67, and 1.94, respectively (P for trend <.001). The relation between tHcy level and CVD hospitalizations was significantly stronger among individuals with preexisting CVD than those without (hospitalization rate ratio per 5-micromol/L tHcy increment, 1.29 vs 1.10; P for interaction,.02). CONCLUSIONS: Plasma tHcy level is a strong predictor of CVD hospitalizations only in elderly individuals, and especially among those with preexisting CVD. Our findings are compatible with the theory that tHcy interacts with conventional CVD risk factors to provoke the acute event of CVD.

Adult↗
PubMed1995

Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study.

OBJECTIVE: To estimate the relations between established cardiovascular risk factors and total homocysteine (tHcy) in plasma. DESIGN: Health examination survey by the Norwegian Health Screening Service in 1992 and 1993. SETTING: General community, Hordaland County of Western Norway. PARTICIPANTS: A total of 7591 men and 8585 women, 40 to 67 years of age, with no history of hypertension, diabetes, coronary heart disease, or cerebrovascular disease were included. MAIN OUTCOME MEASURE: Plasma tHcy level. RESULTS: The level of plasma tHcy was higher in men than in women and increased with age. In subjects 40 to 42 years old, geometric means were 10.8 mumol/L for 5918 men and 9.1 mumol/L for 6348 women. At age 65 to 67 years, the corresponding tHcy values were 12.3 mumol/L (1386 men) and 11.0 mumol/L (1932 women). Plasma tHcy level increased markedly with the daily number of cigarettes smoked in all age groups. Its relation to smoking was particularly strong in women. The combined effect of age, sex, and smoking was striking. Heavy-smoking men aged 65 to 67 years had a mean tHcy level 4.8 mumol/L higher than never-smoking women aged 40 to 42 years. Plasma tHcy level also was positively related to total cholesterol level, blood pressure, and heart rate and inversely related to physical activity. The relations were not substantially changed by multivariate adjustment, including intake of vitamin supplements, fruits, and vegetables. CONCLUSIONS: Elevated plasma tHcy level was associated with major components of the cardiovascular risk profile, ie, male sex, old age, smoking, high blood pressure, elevated cholesterol level, and lack of exercise. These findings should influence future studies on the etiology and pathogenesis of cardiovascular disease.

Adult↗
PubMed2005

Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study.

We examined the relation between plasma total homocysteine (tHcy), folate, vitamin B12, and episodic memory in elderly community-dwelling subjects. A population-based study was conducted in 1992 and 1993, and subjects were re-investigated after 6 years. Plasma analytes were determined on both occasions. At follow-up, memory performance, using the Kendrick Object Learning Test, was investigated in 2,189 subjects (age, 65-67 years at baseline). Subjects with memory deficit (test score, < 25) had higher tHcy and lower folate at follow-up compared with those without memory deficit: 12.6 (95% confidence interval [CI], 12.1, 13.1) versus 11.5 (95% CI, 11.3, 11.6) micromol/L (p < 0.001) for tHcy, and 6.7 (95% CI, 6.2, 7.1) versus 7.6 (95% CI, 7.5, 7.8) nmol/L (p < 0.001) for folate. The risk of memory deficit increased according to quintiles of tHcy both at baseline and at follow-up. A decline in tHcy, or an increase in folate, over a 6-year period was associated with a higher memory test score; and vice versa. These findings indicate that increased plasma tHcy is an independent risk factor for memory deficit both cross-sectionally and prospectively, and that a "favorable" change in folate or tHcy concentrations over time is associated with better memory performance.

Aged↗
PubMed2003

Regulation of reduced-folate transporter-1 (RFT-1) by homocysteine and identity of transport systems for homocysteine uptake in retinal pigment epithelial (RPE) cells.

Reduced-folate transporter-1 (RFT-1) transports reduced-folates, such as N5-methyltetrahydrofolate (MTF), the predominant circulating form of folate. In RPE, RFT-1 is localized to the apical membrane and is thought to transport folate from RPE to photoreceptor cells. Folate is required for DNA, RNA, protein synthesis and the conversion of homocysteine (Hcy) to methionine. Decreased folate levels are associated with increased Hcy levels. In the present study, we asked whether RFT-1 activity in RPE is altered under high Hcy conditions and examined the transport mechanism for Hcy in RPE. Treatment of ARPE-19 cells, a human RPE cell line, with Hcy at concentrations higher than 50 microM led to a significant decrease in RFT-1 activity. This effect increased as the treatment time increased. The inhibitory effect of Hcy on RFT-1 activity was not non-specific, as the activities of several other nutrient transporters were not affected under identical conditions. The effect of Hcy on RFT-1 was associated primarily with a decrease in the maximal velocity with no detectable change in substrate affinity. The decrease in RFT-1 activity was accompanied by parallel changes in RFT-1 mRNA and protein. Uptake of Hcy in ARPE-19 cells occurred via several transport systems, including Na+-independent systems L and b(0,+) and the Na+-dependent systems B0, ATB(0,+) and A. Studies of the interaction of Hcy with one of the cloned transporters (ATB(0,+)) provided direct evidence for the translocation of Hcy across the membrane via the transporter. We conclude that several transport systems operate in ARPE-19 cells for the entry of Hcy and that high levels of Hcy have deleterious effects on the expression and activity of RFT-1 in these cells.

Biological Transport↗
PubMed2002

Elevated homocysteine serum level is associated with low enrichment of homocysteine in coronary arteries of patients with coronary artery disease.

In the present study, we sought to investigate whether elevated serum levels of homocysteine (Hcy), predisposing to endothelial dysfunction during progression of atherosclerosis, were paralleled by increased Hcy concentrations in human coronary arteries. Paraffin sections of coronary arteries were obtained from explanted hearts of cardiac transplant recipients suffering from coronary artery disease (CAD, n=32, mean age=56.6+/-6.8), and from heart donors where transplantation was not performed due to organization-related circumstances (Co, n=6, mean age 25.0+/-10.6), and characterized immunohistochemically for Hcy, CD68, and smooth muscle alpha-actin. Although the CAD group presented with high serum Hcy levels (27.7+/-12.8 micromol/l), the media and intimal layers containing the endothelium showed the lowest enrichment of Hcy (media: 20.8+/-4.4%; intima: 6.1+/-2.3%). Surprisingly, the control group revealed an extensive Hcy enrichment, co-localizing with vascular smooth cells (media: 32.3+/-14.0%; intima: 7.0+/-2.0%). In conclusion, we have provided evidence for a reverse relation between Hcy serum concentration and enrichment of Hcy in coronary arteries of patients with severe CAD, suggesting that Hcy is not likely to be involved directly in atheromatosis development of coronary arteries.

Case-Control Studies↗