Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria.

Precocious atherosclerosis occurs in homocystinuria due to cystathionine beta-synthase deficiency and there is evidence that homocysteine may produce endothelial damage. Mild homocysteinemia has been reported in heterozygotes after methionine loads and it has been suggested that they could have an increased risk of atherogenesis. We measured plasma amino acids before and after a methionine load (100 mg per kg) in 17 obligatory heterozygotes, in 20 men under 50 yr with established ischemic heart disease, and in matched controls, to determine whether methionine loading allows identification of heterozygotes, and whether there is an altered rate of methionine metabolism in patients with premature coronary artery disease. The obligate heterozygotes had higher mean plasma concentrations of methionine and total homocysteine at 4, 8 and 12 hours after the load than their controls, and lower concentrations of total cysteine and taurine in fasting and all post load samples; however, there was considerable overlap of measurements in heterozygotes and their controls even when differential weightings were applied. There were no differences in mean plasma concentrations of methionine, total homocysteine or total cysteine between the patients with ischemic heart disease and their controls at any measurement point. However, two patients with premature coronary artery disease, identical twins, had persistent elevation of total plasma homocysteine and an exaggerated homocysteine response to methionine. Oral folate restored homocysteine concentrations before and after methionine to normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Accumulation of sulphur-containing amino acids including cysteine-homocysteine in patients on maintenance haemodialysis.

1. Plasma sulphur-containing amino acids were measured in 19 patients with renal failure on chronic haemodialysis and in 22 normal subjects, to determine the rate of accumulation of these amino acids in chronic azotaemia. 2. Cysteine--homocysteine mixed disulphide was significantly increased in patients before dialysis and homocysteine was detected in low concentration in 10 patients. Cystine and taurine were also increased. Changes in other neutral and acidic amino acids were similar to those reported in chronic renal insufficiency. 3. In 3--4 h of dialysis serum creatinine was decreased by a mean of 55%, cysteine--homocysteine by 41% and cystine by 58.5% (P less than 0.001 for each). Methionine concentrations were normal throughout. 4. We conclude that sulphur-containing amino acids, except methionine, accumulate in chronic renal failure as rapidly as creatinine.

Cysteine-homocysteine mixed disulphide: differing plasma concentrations in normal men and women.

1. The mixed disulphide of cysteine and homocysteine is known always to be present in the plasma of patients with homocystinuria, an abnormality of methionine metabolism. Recently we have shown that it is also detectable in low concentration in the plasma of normal fasting man. In the present study we measured mixed disulphide concentrations after an overnight fast in 24 normal men and compared the findings with those obtained in 24 normal premenopausal women of similar age. 2. The mean value for men (+/- SD) of 3.3 +/- 0.8 micromol/l was significantly higher than that for women (2.4 +/- 0.7 micromol/l; P less than 0.001). Of the other neutral and acidic amino acids measured mean values for leucine, isoleucine and valine (P less than 0.001) and cystine (P less than 0.01) were also higher in the men but methionine concentrations were not significantly different. 3. The higher branched-chain amino acid concentrations in men could be related to larger muscle bulk and protein intake, but the higher cysteine-homocysteine mixed disulphide concentrations are consistent with differences in methionine metabolism between men and women under the age of 50 years.

Sulphr containing amino acids in chronic renal failure with particular reference to homocystine and cysteine-homocysteine mixed disulphide.

We measured plasma sulphur amino acids in twenty-two patients with chronic renal failure and compared the findings with those obtained in twenty-two normal subjects. In fasting blood (08.00 hours) cysteine-homocysteine mixed disulphide was significantly increased in the renal patients, mean values (+/- SD) being 8.2 +/- 3.4 and 3.1 +/- 1.0 mumol/l respectively (P less than 0.001). The increase was positively correlated with reduced renal function, as assessed by serum creatinine (r = 0.62; P less than 0.01). Homocystine was detected in nineteen patients, the mean concentration (+/- SD) being 1.7 +/- 0.6 mumol/l; it was not found in any normal subject. Methionine levels were not different but there were significant increases in cystine (P less than 0.001) and taurine (P less than 0.05) in the patients. Similar values for these amino acids were found in a second blood sample drawn at 16.00 hours. Changes in the other neutral and acidic amino acids measured were in agreement with those reported in chronic azotaemia. We concluded that plasma levels of all the principal sulphur amino acids except methionine are elevated in chronic renal failure emphasizing the importance of the kidney in sulphur excretion. Prolonged accumulation of homocysteine and cysteine-homocysteine mixed disulphide may be relevant to the development of accelerated vascular disease in patients with chronic renal failure by producing endothelial damage.

The detection of cysteine-homocysteine mixed disulphide in plasma of normal fasting man.

Cysteine-homocysteine mixed disulphide, formed in the degradation of methionine, is detected routinely in the plasma of fasting patients homozygous for homocystinuria and in some obligate heteroxygotes. It has not hitherto been identified in the plasma of normal fasting man. Using a highly cross-linked resin with lithium citrate buffers on a JEOL. Amino Acid Analyser, we have detected the mixed disulphide in every one of the plasma samples from twenty normal fasting subjects. The mean concentration was 3.25 mumol/l (SD 0.85, N = 20), with a range of from 1.68 to 4.85 mumol/l. The other neutral and acidic amino acids were within the accepted normal range. The study shows that circulating homocysteine is normally not immediately transformed to cystathionine or remethylated to methionine; some combines with cysteine to form measurable amounts of mixed disulphide. Since homocysteine may produce endothelial damage, the present findings could be relevant to an understanding of the pathogenesis of vascular disease.

A third dipeptide carrier system typified by l-prolyl-lhydroxyproline and independent of l-leucyl and beta-alanyl dipeptides in rat gut loops.

1. The intestinal transport of L-prolyl-L-hydroxyproline (10 mmol/l) was investigated in rat small gut loops in vivo under pentobarbitone anaesthesia. Osmolality of test solutions was adjusted to eliminate any positive effect of solvent drag on disappearance of solutes from the lumen. 2. L-Leucylglycine and beta-alanyl-L-histidine (carnosine), representative members of two distinctly different dipeptide transport groups previously delineated, were tested for competitive action on L-prolyl-L-hydroxyproline uptake at ten times equimolar concentration (100 mmol/l), but were found to have no effect on the carrier system. 3. L-Prolyl-L-hydroxyproline uptake was markedly blocked by other L-prolyl dipeptides, indicating that they shared a common carrier system. Disappearance of L-prolyl-L-hydroxyproline from the gut lumen was reduced from 48% 15 min-1 10 cm-1 (control, containing 70 mmol/l mannitol) to 11% or 20% in the presence of L-prolylglycine (100 mmol/l) or L-prolyl-L-leucine (25 mmol/l), respectively. 4. It was concluded that at least three separate dipeptide carrier protein systems exist in the rat small gut, the disappearance of L-prolyl-L-hydroxyproline from the gut lumen being inhibited by two other L-prolyl dipeptides but not by L-leucyl or beta-alanyl dipeptides.

Depression of jejunal dipeptide transport by pyridoxine deficiency in the rat.

Three dipeptides (L-alanyl-L-alanine, beta-alanyl-L-histidine and L-prolylglycine), representative of distinctly different transport groups, and a dicarboxylic acid dipeptide (L-glutamyl-L-glutamic acid) showed a quantitatively equivalent decrease of absorption (mean difference, 12% disappearance 15 min-1 5 cm-1) from jejunal loops in vivo in pyridoxine deficient rats, compared with pyridoxine-repleted controls. Analysis of results for seven dipeptides, including three studied previously, indicated that pyridoxine deficiency caused a general or non-specific reduction in dipeptide transport, similar for all dipeptides. Decrease in dipeptide transport in vitamin deficiency ran parallel to, but was significantly less than, the decrease in amino acid transport, suggesting in theory involvement of pyridoxine in a common cellular efflux mechanism or, less likely, in the energetics of active transport.