Biochemical effects of methotrexate in isolated hepatocytes in relation to its steatogenic activity.

Methotrexate (MTX) is known to induce steatosis in humans. The effect of MTX on the synthesis and secretion of triglycerides and proteins as well as on RNA synthesis were evaluated using isolated rat hepatocytes in suspension as an experimental model. MTX significantly inhibited protein synthesis (48% inhibition after 180 min) and RNA synthesis (72% inhibition after 180 min) at 10(-3)m but not at a concentration of 10(-4)m. Protein secretion was not affected by MTX at any of the concentrations tested. At 10(-3)m, but not at 10(-4)m, MTX inhibited triglyceride secretion (44% inhibition after 180 min). At both 10(-3) and 10(-4)m, MTX significantly depleted the intracellular triglyceride, and significantly inhibited total triglyceride esterification (18 and 28% inhibition at 10(-4) and 10(-3)m-MTX, respectively). These data support the hypothesis that MTX affects protein and fatty-acid metabolism.