Acute and long-term effects of high-dose methotrexate treatment on homocysteine in plasma and urine.

The amino acid, homocysteine, is not supplied by food but is a product formed by cleavage of S-adenosylhomocysteine; a product of transmethylation. Homocysteine is further salvaged to methionine. Since this reaction is in most tissues dependent on 5-methyltetrahydrofolate, we investigated the effect of the antifolate drug, methotrexate (MTX), on homocysteine in patients treated with this drug against cancer. Free and protein-bound homocysteine in plasma and urinary excretion of this amino acid were monitored in seven patients before, during, and after infusion with MTX (1-13.6 g). Each patient was investigated during one to five consecutive MTX treatments, which were separated by intervals of 1 to 4 weeks. Three components of the homocysteine response could be distinguished. An acute effect appeared after a lag period of about 6 h, lasted for about 24 h, and was characterized by a transient increase in free and protein-bound homocysteine and a concomitant increase in urinary excretion of homocysteine. Some patients showed a marked plasma response, whereas in others, enhancement of urinary excretion predominated. A long-term effect developed within 48-72 h after each infusion and was characterized by a progressive decrease in both plasma homocysteine and urinary excretion of homocysteine to amounts below those observed prior to the infusion. This effect lasted for at least 4 weeks. In this way the amount of homocysteine in plasma and urine decreased as a function of the number of MTX infusions. This long-term effect was associated with a decrease in acute homocysteine response in plasma and/or urine. Notably, MTX induced no acute or long-term effect on plasma methionine, suggesting that the homocysteine response is not caused by an imbalance in methionine metabolism due to malignant disease or chemotherapy. The cause and possible consequences of altered homocysteine metabolism during MTX therapy are discussed.