Characteristics of the Accumulation of Methotrexate Polyglutamate Derivatives in Ehrlich Ascites Tumor Cells and Isolated Rat Hepatocytes
The intracellular synthesis and retention of polygammaglutamyl derivatives of methotrexate and their interactions with H2folate reductase was evaluated in the Ehrlich ascites tumor cell and the isolated rat hepatocyte. Methotrexate polyglutamates were detected within 15 minutes in hepatocytes exposed to 1 µM methotrexate, and continued to accumulate for at least 60 minutes producing a large transmembrane gradient. These derivatives appeared to be preferentially retained within the cell even under conditions where release of intracellular methotrexate was induced by dibutyryl cyclic AMP or isobutyl methyl xanthine. Deoxycholate and bromo-sulfophthalein, compounds which inhibited methotrexate influx into hepatocytes, reduced the ratio of methotrexate polyglutamates to methotrexate, suggesting that these agents also inhibit the metabolism of methotrexate.
KeywordsRose BENGAL Isobutyl Methyl Xanthine Ehrlich Ascites Tumor Cell Polyglutamate Derivative Glutamate Derivative
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