The effect of methotrexate on homocysteine methylating agents in rat liver.

Methotrexate (MTX) was administered to rats in a time course study throughout a 4-month period. Despite an inhibition of the hepatic dihydrofolate reductase by 88 to 90% in these animals, the body weights and liver weights of the treated animals did not vary from those of the pair-fed controls during this time course, and the livers showed no fatty infiltration as demonstrated by triglyceride analyses. The prime methylating agent of homocysteine, N5 methyltetrahydrofolate, progressively increased in control livers throughout the experimental period; however, MTX impaired the increases at the 2- and 4-month periods in the treated animals. Hepatic betaine, the secondary methylator of homocysteine in the liver, also increased in the controls during the experimental period. These increases were also impaired in the MTX-treated animals. These data suggest that betaine may compensate for N5 methyltetrahydrofolate as a methylating substance when folate metabolism is antagonized in rat liver.