tCys Concentrations Research Articles

Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose-finding study.

To investigate whether mesna-sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine. Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; Poverall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC0-12h decreased (Ptrend < .001), and urine tCys excretion increased (Ptrend = .004). Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.

S-Adenosylmethionine Is Associated with Fat Mass and Truncal Adiposity in Older Adults

S-adenosylmethionine (SAM) is synthesized from methionine, which is abundant in animal-derived protein, in an energy-consuming reaction. SAM and S-adenosylhomocysteine (SAH) correlate with body mass index (BMI). Plasma total concentration of the SAM-associated product cysteine (tCys) correlates with fat mass in humans and cysteine promotes adiposity in animals. In a cross-sectional study of 610 participants, we investigated whether SAM and SAH are associated with BMI via lean mass or fat mass and dietary protein sources as determinants of SAM and tCys concentrations. Plasma SAM was not associated with lean mass, but mean adjusted fat mass increased from 24 kg (95% CI: 22.6, 25.1) to 30 kg (95% CI: 28.7, 31.3) across SAM quartiles (P < 0.001) and trunk fat:total fat ratio increased from 0.48 to 0.52 (P < 0.001). Erythrocyte SAM was also positively associated with fat mass and trunk fat:total fat ratio. The association of SAM with fat mass was not weakened by adjustment for serum tCys, lipids, creatinine, or dietary or lifestyle confounders. Concentrations of the SAM precursor, methionine, and the SAM product, SAH, were not independently associated with adiposity. Intake of animal-derived protein was not related to serum methionine but was positively associated with plasma SAM (partial r = 0.11) and serum tCys (partial r = 0.13; P < 0.05 for both after adjustment for age, gender, and total energy intake). In conclusion, plasma SAM, but not methionine, is independently associated with fat mass and truncal adiposity, suggesting increased conversion of methionine to SAM in obese individuals. Prospective studies are needed to investigate the interactions among dietary energy and animal protein content, SAM concentrations, and change in body weight and cardiometabolic risk.

Dietary protein and plasma total homocysteine, cysteine concentrations in coronary angiographic subjects

BackgroundDietary patterns are associated with plasma total homocysteine (tHcy) concentrations in healthy populations, but the associations between dietary protein and tHcy, total cysteine (tCys) in high risk populations are unclear. We therefore examined the association between dietary protein and tHcy and tCys concentrations in coronary angiographic subjects.MethodsWe conducted a cross-sectional study of 1015 Chinese patients who underwent coronary angiography (40–85 y old). With the use of food-frequency questionnaires, we divided the total protein intakes into high animal-protein and high plant-protein diets. Circulating concentrations of tHcy and tCys were simultaneously measured by high-performance liquid chromatography with fluorescence detection.ResultsWe found that high animal-protein diet was positively associated with hyperhomocysteinemia after adjustment for potential confounders, with the subjects in the highest quartile of intake having the greatest increase in risk (OR: 4.14, 95% CI: 2.67-6.43), whereas high plant-protein diet was inversely related to hyperhomocysteinemia, with a higher intake being protective. Compared with the first quartile of intake, the adjusted OR was 0.59 (95% CI: 0.38-0.91) for the fourth quartile. The total protein intake was positively associated with the risk of hypercysteinemia and the participants in highest quartile had significant OR of 1.69 (95% CI: 1.02-2.87) compared with those in lowest quartile. In multivariate linear regression analyses, high animal-protein and total-protein intakes were positively associated with plasma tHcy and tCys concentrations. The plant-protein intake was a negative determinant of plasma tHcy concentrations.ConclusionsHigh animal-protein diet was positively associated with high tHcy concentrations, whereas high plant-protein diet was inversely associated with tHcy concentrations. Furthermore the total protein intake was strongly related to tCys concentrations.

An Encapsulated Juice Powder Concentrate Improves Markers of Pulmonary Function and Cardiovascular Risk Factors in Heavy Smokers

Objective: Cigarette smoking is associated with reduced pulmonary function and increased risk factors for cardiovascular disease. This randomized placebo-controlled double-blind study evaluated the effects of two different combinations of mixed fruit and vegetable juice powder concentrate (Juice Plus+, NSA, Collierville, TN) on heavy smokers. Methods: At baseline (T 0) and after 3 months’ supplementation (T 1), pulmonary function parameters and cardiovascular risk factors—that is, plasma total homocysteine (tHcy) with related B vitamins and cysteine (tCys) concentrations—were assessed in 75 apparently healthy smokers (aged 49.2 ± 10.6 years, >20 cigarettes/d, duration ≥10 years) randomized into 3 groups: placebo (P), fruit/vegetable (FV) and fruit/vegetable/berry (FVB). Results: T 0: most smokers showed abnormalities in tHcy and tCys concentrations. T 1: respiratory function was unchanged in P and slightly, but not significantly, improved in FV, whereas FVB showed a significant improvement in forced expiratory flow at 25% (FEF25; p < 0.0001 vs P and FV) and significant improvement in CO diffusion lung/alveolar volume (DLCO/VA). FV and FVB (50%) showed significant reduction in tHcy and tCys compared to T 0 ( p < 0.0001) and P ( p < 0.0001). Conclusions: At T 1, both supplemented groups, but to a greater extent the FVB group, showed improvements in some pulmonary parameters, cardiovascular risk factors, and folate status. The beneficial effects of Juice Plus+ supplementation could potentially help smokers, even if smoking cessation is advisable.

Effect of bariatric surgery on sulphur amino acids and glutamate

Plasma total cysteine (tCys) concentrations are associated with BMI. To study the relationship between tCys and BMI, we monitored the changes in serum concentrations of tCys and metabolically related compounds in sixty obese patients (BMI 50-60 kg/m(2)) from before to 1 year after either gastric bypass surgery (mean 30 % weight loss) or duodenal switch surgery (mean 41 % weight loss). A total of fifty-eight healthy persons (BMI 17-31 kg/m(2)) served as controls. Before surgery, obese patients had modestly (approximately 17 %) higher mean serum tCys, and markedly (>2-fold) higher glutamate concentrations, than controls (P ≤ 0·001 for both). Serial examinations after surgery revealed that gastric bypass patients had no change in tCys concentrations (P = 0·22), while duodenal switch patients showed a modest (approximately 12 %) but significant decrease in tCys (P < 0·001). Total homocysteine concentrations increased in duodenal switch patients but not in gastric bypass patients. Independent of surgery type, serum concentrations of methionine and cystathionine decreased (P < 0·05 for both), while serum glutathione and taurine remained stable. Glutamate concentrations declined, as did γ-glutamyltransferase activity (P < 0·001 for both). These results show that despite 30 % weight loss, and decreases in methionine, cystathionine and glutamate, there was no significant change in serum tCys in patients after gastric bypass surgery. The decrease in tCys in patients undergoing duodenal switch could be related to malabsorption. The present findings do not suggest that BMI is a causal determinant of plasma tCys.

High-throughput and simultaneous measurement of homocysteine and cysteine in human plasma and urine by liquid chromatography–electrospray tandem mass spectrometry

Total homocysteine (tHcy) and cysteine (tCys) concentrations in biological fluids are routinely used in the clinical diagnosis of genetic and metabolic diseases, and this necessitates the development of rapid and sensitive methods for quantification. Liquid chromatography–electrospray tandem mass spectrometry (LC–MS/MS) was used to measure tHcy and tCys in 23 plasma and 21 urine samples from healthy adults and 14 urine samples from healthy children. The results were compared with a standard high-performance liquid chromatography (HPLC) method. The coefficient of variation (CV) for the LC–MS/MS method ranged from 2.9% to 6.1% for the intraassay and 4.8% to 6.4% for the interassay. Mean recoveries were close to 100% for both plasma and urinary tHcy and tCys. The mean plasma tHcy and tCys concentrations in healthy adults were 8.62 and 261.40μmol/L, respectively. The mean urinary tHcy and tCys in adults were 0.98 and 22.60μmol/mmol creatinine, respectively. The mean urinary tHcy and tCys in children were 1.17 and 27.43μmol/mmol creatinine, respectively. Bland–Altman difference plots of method comparison between LC–MS/MS and HPLC showed good agreement in plasma and urinary tHcy and tCys concentrations. Our method is suitable for rapid measurements, and the reported urinary values in children will help to develop a pediatric reference range for clinical use.

Physical Training Decreases Total Plasma Homocysteine and Cysteine in Middle-Aged Subjects

Aims: The aim of this study was to evaluate whether endurance exercise in middle-aged men induces changes in plasma total homocysteine (tHcy) and total cysteine (tCys), and whether these changes depend on the diet especially on vitamin B₆, folic acid and vitamin B₁₂ intakes. Methods: Twelve trained subjects (52.33 ± 2.4 years) and twelve untrained subjects (56.23 ± 0.9 years) volunteered for the present study. tHcy and tCys were measured with high-pressure liquid chromatography at rest in both groups and during an incremental exercise performed on a cycle ergometer until exhaustion in the trained subjects. Results: At baseline homocysteinemia and cysteinemia were lower in trained subjects (7.48 ± 0.4 and 183.45 ± 13.6 µmol/l) compared with untrained subjects (9.79 ± 0.4 µmol/l, p < 0.001; 229.01 ±14.7 µmol/l, p < 0.05, respectively). Incremental exercise also induced a decrease in tHcy and tCys concentrations. Moreover, tHcy concentration was negatively related to the folic acid and B₁₂ intakes in untrained (r = –0.589, p < 0.05; r = –0.580, p < 0.05, respectively) as well as in trained groups (r = –0.709, p < 0.01; r = –0.731, p < 0.01, respectively) whereas no correlation between tCys and vitamin in the diet was observed. Conclusion: This study demonstrates that the combined effects of a chronic physical exercise and a high folate and vitamin B₁₂ intake could be responsible for the reduction of plasma tHcy and tCys concentrations that might be a key for the prevention of many diseases.

Plasma total cysteine, mortality, and cardiovascular disease hospitalizations: the Hordaland Homocysteine Study.

We have previously reported a positive association between tHcy and mortality and cardiovascular disease (CVD) hospitalizations in the Hordaland Homocysteine Study cohort. Using the same data set, we assessed the relationship between plasma total cysteine (tCys) and mortality from all causes and from cardiovascular and noncardiovascular conditions, and the association between tCys and the risk of hospitalizations from CVD. We measured plasma tCys in blood samples from 12,595 men and women 40-42 years of age and from 4766 men and women 65-67 years of age, collected as part of the Hordaland Homocysteine Study in the year 1992-1993. Follow-up data on mortality were collected through 1999. Data on CVD hospitalizations were collected from hospital records up to May 31, 1998. After a follow-up time of 6.6-7.6 years, there were a total of 610 deaths, of which 243 were cardiovascular deaths and 367 were noncardiovascular deaths. There was no association between tCys and all-cause, cardiovascular, or noncardiovascular mortality. When we used tCys values <247.6 micromol/L (lowest quartile) as the reference category, the adjusted mortality ratio (MR) for all-cause mortality at tCys concentrations of 247.6-270.79, 270.8-295.79, and > or =295.8 micromol/L (highest quartile) were 1.0, 0.9, and 1.0, respectively. The adjusted MRs for cardiovascular mortality were 1.0, 1.1, and 1.1, respectively. There were no associations between tCys and 1275 CVD hospitalizations, except that tCys was significantly associated with hospitalizations from coronary artery bypass grafting. Plasma tCys is not associated with mortality or CVD hospitalizations.

Plasma total cysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study

Total homocysteine (tHcy) is associated with pregnancy complications and adverse pregnancy outcomes. The associations of plasma total cysteine (tCys) with such outcomes have not been investigated in large populations. We investigated the association between plasma tCys and pregnancy complications, congenital malformations, and other adverse pregnancy outcomes. The plasma tCys concentrations of 5883 women aged 40-42 y that were measured in 1992-1993 during a cardiovascular health screening were compared with the outcomes and complications of 14492 pregnancies in the same women that were registered in the Medical Birth Registry of Norway from 1967 to 1996. After adjustment for parity, mother's age, tHcy, total cholesterol, body mass index, smoking, and coffee drinking, high plasma tCys concentrations (above the 95th percentile) were associated with significantly higher risks of preeclampsia [n = 342; odds ratio (OR): 1.6; 95% CI: 1.1, 2.4; P = 0.03], premature delivery (n = 774; OR: 1.8; 95% CI: 1.3, 2.5; P = 0.001), and very low birth weight (n = 175; OR: 2.0; 95% CI: 1.1, 3.9; P = 0.03) than were lower plasma tCys concentrations. tCys was not associated with the risk of placental abruption. High tCys concentrations showed a weak association with congenital malformations and stillbirths with birth weight <1500 g. The associations were independent of the tHcy concentrations. High tCys concentrations were associated with risks of preeclampsia, premature delivery, and low birth weight.

Predictors of change in plasma total cysteine: longitudinal findings from the Hordaland homocysteine study.

Total cysteine (tCys) in plasma has recently been linked to cardiovascular risk and is also associated with cardiovascular risk factors, including body mass index (BMI) and cholesterol. Changes and predictors of change in tCys concentrations over a mean follow-up time of 6.0 (5.2-7.2) years were assessed in this study. Baseline data from the Hordaland Homocysteine Study recorded in 1992-1993 included tCys, total homocysteine (tHcy), and various lifestyle and cardiovascular risk factors. In 1998-1999, the same measurements were repeated in 3,732 individuals born in 1950-1951 and 3,339 individuals born in 1925-1927. Most of the statistical analyses were done separately in the four age and sex groups. The overall mean values of tCys were higher at follow-up [mean (SD), 296 (41) micro mol/L] than at baseline [278 (36.5) micro mol/L]; P <0.0001. The mean percentage of increase in tCys in the different age and sex groups ranged from 4.9% to 8.5%. There was a significant correlation between the tCys values measured on the two occasions (Spearman correlation coefficient, 0.55-0.59 in the different age and sex groups; P <0.0001). The change in tCys correlated with changes in BMI, cholesterol, and diastolic blood pressure in the younger age group, whereas only changes in BMI predicted changes in tCys in the older age group. tCys increased in the 6 years between the two measurements. Factors related to the baseline tCys values, including BMI and the change in BMI, predicted the tCys changes over time.

Association of hyperhomocysteinemia with plasma sulfate and urine sulfate excretion in patients with progressive renal disease

Background: Plasma total homocysteine (tHcy) level is increased in patients with renal disease, parallel to serum creatinine concentration. In renal failure, the final product of sulfated amino acid metabolism, sulfate, also accumulates as renal function declines. We hypothesized that the elevation in sulfate level could cause hyperhomocysteinemia and tested the relation between tHcy level and both urinary excretion and plasma levels of sulfate. Methods: Forty patients with renal disease were divided into three groups: patients without renal failure (nRF; creatinine clearance [CCr] ≥ 80 mL/min/1.73 m2 [≥1.33 mL/s/1.73 m2]), patients with mild renal failure (mRF; 80 > CCr ≥ 25 mL/min/1.73 m2 [1.33 > CCr ≥ 0.42 mL/s/1.73 m2]), and patients with severe renal failure (sRF; CCr < 25 mL/min/1.73 m2 [<0.42 mL/s/1.73 m2]). Daily urinary excretion and plasma levels of tHcy, total cysteine (tCys), and sulfate were measured. A healthy control (HC) group also was tested. Serum methionine, taurine, vitamin B12, and folate levels also were determined in patients with renal disease. Results: Plasma tHcy and sulfate concentrations in the groups with mRF and sRF were greater than in the HC group. Plasma tCys concentrations in the mRF and sRF groups were greater than in the nRF group. Daily urinary Hcy and Cys excretion did not differ among the four groups. Daily urine sulfate and urea nitrogen excretion in the sRF group were significantly less than in the HC and nRF groups. Multiple regression analyses showed that plasma creatinine (β = 0.40) and sulfate (β = 0.43) levels were independently associated with plasma Hcy level; among urine parameters, only daily urine sulfate excretion (β = −0.52) was independently associated with plasma Hcy level. Conclusion: The elevated plasma sulfate level, in accordance with renal function, is associated with plasma tHcy level. Decreased sulfate excretion, which might parallel the intake of sulfated amino acid or protein, may increase tHcy levels. Am J Kidney Dis 40:909-915. © 2002 by the National Kidney Foundation, Inc.

A C677T mutation in the methylenetetrahydrofolate reductase gene modifies serum cysteine in dialysis patients

Patients undergoing hemodialysis have impaired metabolism of such sulfur-containing amino acids as cysteine (Cys) and homocysteine (Hcy), which may lead to accelerated atherosclerosis. Considering that Cys is mainly synthesized from Hcy, a common C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene may affect the serum total Cys (tCys) concentration, as well as total Hcy (tHcy) concentration, through reduced remethylation of Hcy to methionine, even in hemodialysis patients. To identify the independent determinants for the tCys concentration in dialysis patients, we determined MTHFR C/T genotypes and serum concentrations of tHcy, tCys, and vitamins as cofactors in 464 hemodialysis patients. Serum tCys concentration was positively associated with serum tHcy concentration and negatively associated with the MTHFR mutation, although the mutation correlated positively with serum tHcy concentration. Slopes of regression lines relating tHcy and tCys concentrations differed between the MTHFR genotypes, and the relationship was strengthened with a decreasing number of T alleles. Additionally, serum concentrations of folate and vitamin B12 correlated positively with tCys concentration, whereas they correlated negatively with tHcy concentration. These findings suggest that the MTHFR mutation is an independent predictor for serum tCys concentrations in hemodialysis patients and that a tCys-decreasing effect of the mutation may arise largely from its attenuation of the positive Cys-Hcy correlation. The tCys-increasing effect of folate and vitamin B12 appears to be linked to their enhancement of Hcy remethylation.

Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus

The plasma concentrations of total homocysteine (tHcy) and total cysteine (tCys) are determined by intracellular metabolism and by renal plasma clearance, and we hypothesized that glomerular filtration is a major determinant of plasma tHcy and tCys. We studied the relationships between the glomerular filtration rate (GFR) and plasma tHcy and tCys in populations of diabetic patients with particularly wide ranges of GFR. We measured GFR, urine albumin excretion rate (UAER), plasma tHcy, tCys, methionine, vitamin B12, folate, C-peptide, and routine parameters in 50 insulin-dependent diabetes mellitus (IDDM) and 30 non-insulin-dependent diabetes mellitus (NIDDM) patients. All patients underwent intensive insulin treatment and had a serum creatinine concentration below 115 micromol/liter. Mean plasma tHcy in diabetic patients (0.1 micromol/liter) was lower than in normal persons (11.1 micromol/liter, P = 0.0014). Mean plasma tCys in diabetic patients (266.1 micromol/liter) was also lower than in normal persons (281.9 micromol/liter, P = 0.0005). Seventy-three percent of the diabetic patients had relative hyperfiltration. Plasma tHcy and tCys were closely and independently associated with GFR, serum folate, and serum B12. However, plasma tHcy was not independently associated with any of the 22 other variables tested, including age, serum creatinine concentration, UAER, total daily insulin dose, and glycemic control. Glomerular filtration rate is an independent determinant of plasma tHcy and tCys concentrations, and GFR is rate limiting for renal clearance of both homocysteine and cysteine in diabetic patients without overt nephropathy. Declining GFR explains the age-related increase in plasma tHcy, and hyperfiltration explains the lower than normal mean plasma tHcy and tCys concentrations in populations of diabetic patients.