Effect of methionine loading on 5-methyltetrahydrofolate, S-adenosylmethionine and S-adenosylhomocysteine in plasma of healthy humans.

1. Elevated plasma homocysteine concentration, either in the fasting state or after methionine loading, is an independent risk factor for vascular disease in man. Methionine loading has been used to investigate impaired methionine metabolism, especially of the trans-sulphuration pathway, but most studies have focused on changes in homocysteine. 2. We investigated the effect of methionine excess on total plasma homocysteine, 5-methyltetrahydrofolate (which is the active form of folate in the remethylation of homocysteine to methionine), S-adenosyl-methionine (the first metabolite of methionine) and S-adenosylmethionine) (the demethylated product of S-adenosylmethionine) over 24h in 12 healthy subjects. 3. As well as the expected increase in homocysteine (from 8.0 +/- 1.3 to 32.6 +/- 10.3 mumol/l, mean +/- SD, P < 0.001), S-adenosylmethionine showed a significant transient increase (from 37.9 +/- 25.0 to 240.3 +/- 109.2 nmol/l, P < 0.001), which correlated well with homocysteine (r2 = 0.92, P < 0.001). 5-Methyltetrahydrofolate values decreased significantly (from 23.2 +/- 7.2 to 13.1 +/- 2.9 nmol/l, P < 0.01), and gradually returned to baseline levels after 24h. No significant change over the time of measurement was found for S-adenosylhomocysteine. 4. The sequence of metabolic changes observed in this study strongly suggests that a change in either homocysteine or S-adenosylmethionine may cause a reduction in 5-methyltetrahydrofolate. This must be considered in evaluating the relationship between folate and homocysteine in vascular disease. The metabolic relationships illustrated in this study should be evaluated in the search for pathogenetic mechanisms of mild hyperhomocysteinaemia and vascular disease.