Methionine plasma concentration

In a study of plasma concentrations of 33 amino acids, 159 subjects were recruited, of whom 107 were ecstasy users (93). The subjects were grouped according to cumulative lifetime use under 100 tablets (n = 34), 100-499 tablets (n = 42), 500-2500 tablets (n = 30), abstinent subjects (n = 11), and never users (n = 41). All were ecstasy free for at least 3 days, as verified by toxicological analysis. In 49% of the users, the time to the last use of ecstasy was 1 month or less. There were significant reductions in the serum concentrations of phosphoserine, glutamate, citrul-line, methionine, tyrosine, and histidine. Based on findings from other studies, the authors speculated that the reductions in serine and methionine may underlie psychosis associated with the use of ecstasy. Reduced glutamate may also add to the burden of psychiatric symptoms in ecstasy users. 

As shown in Table 9.5, there are a number of indices of vitamin Be status available plasma concentrations of the vitamin, urinary excretion of 4-pyridoxic acid, activation of erythrocyte aminotransferases by pyridoxal phosphate added in vitro, and the ability to metabolize test doses of tryptophan and methionine. None is wholly satisfactory and where more than one index has been used in population studies, there is poor agreement between the different methods (Bender, 1989b Bates et al., 1999a). 

Early studies of vitamin Be requirements used the development of abnormalities of tryptophan or methionine metabolism during depletion, and normalization during repletion with graded intakes of the vitamin. Although tryptophan and methionine load tests are unreliable as indices of vitamin Be status in epidemiological studies (Section 9.5.4 and Section 9.5.5), under the controlled conditions of depletion/repletion studies they do give a useful indication of the state of vitamin Be nutrition. More recent studies have used more sensitive indices of status, including the plasma concentration of pyridoxal phosphate, urinary excretion of 4-pyridoxic acid, and erythrocyte transaminase activation coefficient. 

Epidemiological smdies suggest that hyperhomocysteineima is most significantly correlated with low folate status, but there is also a significant association with low vitamin Bg status (SeUiub et al., 1993). Trials of supplementation have shown that whereas folate supplements lower fasting homocysteine in moderately hyperhomocysteinemic subjects, supplements of 10 mg per day of vitamin Bg have no effect, although supplements do reduce the peak plasma concentration of homocysteine after a test dose of methionine (Ubbink et al., 1994 Ubbink, 1997 Dierkes et al., 1998). This can probably be explained on the basis of the kinetics of the enzymes involved the of cystathionine... 

Deficiency of vitamins Bg, B12, or folate are aU associated with elevated plasma homocysteine, with vitamin Bg deficiency as a result of impaired activity of cystathionine synthetase (Section 9.5.5) and folate and vitamin B12 as a result of impaired activity of methionine synthetase (Section 10.3.4). In subjects with apparently adequate intakes of vitamins Bg and B12, supplements of these two vitamins have little or no effect on fasting plasma homocysteine, although additional vitamin Bg reduces the plasma concentration of homocysteine after a test dose of methionine. By contrast, supplements of... 

Taurine is a dietary essential in the cat, which is an obligate carnivore with a limited capacity for taurine synthesis from cysteine. On a taurine-free diet, neither supplementary methionine nor cysteine will maintain normal plasma concentrations of taurine, because cats have an alternative pathway of cysteine metabolism reaction with mevalonic acid to yield felinine (3-hydroxy-1,1-dimethylpropyl-cysteine), which is excreted in the urine. The activity of cysteine sulfinic acid decarboxylase in cat liver is very low. 

The biochemical phenotype of homocystinuria is characterized by increased plasma concentrations of methionine, free homocysteine and cysteine-homocysteine disulfide, together with low cystine (Figure 55-6, C). Determination of total homocysteine after treatment of the sample with... 

Because the hver metabohzes the aromatic amino acids (i.e., phenylalanine, tyrosine, and tryptophan), methionine, and glutamine, the plasma concentrations of these amino acids are elevated in cirrhotic patients. Plasma concentrations of the branched-chain amino acids (BCAAs) (i.e., valine, leucine, and isoleucine) often are depressed because these amino acids are metabohzed by skeletal muscle. This altered plasma aminogram contributes to the development of hepatic encephalopathy. 

A number of studies have shown that while folate supplements lower fasting homocysteine in moderately hyperhomocysteinemic subjects, lOmg/day vitamin Bg has no effect, although they do reduce the peak plasma concentration of homocysteine following a test dose of methionine. 

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

Homocystinuria can be treated in some cases by the administration of pyridoxine (vitamin Bs), which is a cofactor for the cystathionine synthase reaction. Some patients respond to the administration of pharmacological doses of pyridoxine (25-100 mg daily) with a reduction of plasma homocysteine and methionine. Pyridoxine responsiveness appears to be hereditary, with sibs tending to show a concordant pattern and a milder clinical syndrome. Pyridoxine sensitivity can be documented by enzyme assay in skin fibroblasts. The precise biochemical mechanism of the pyridoxine effect is not well understood but it may not reflect a mutation resulting in diminished affinity of the enzyme for cofactor, because even high concentrations of pyridoxal phosphate do not restore mutant enzyme activity to a control level. 

Figure 22.7 Homocysteine formation from methionine and formation of thiolactone from homocysteine. The homocysteine concentration depends upon a balance between the activities of homocysteine methyltransferase (methionine synthase) and cystathionine p-synthase. Both these enzymes require vitamin B12, so a deficiency can lead to an increase in the plasma level of homocysteine. (For details of these reactions, see Chapter 15.) Homocysteine oxidises spontaneously to form thiolactone, which can damage cell membrane.

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