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Formation of Methotrexate Polyglutamates in Rat Hepatocytes¹

Departments of Medicine and Pharmacology, Medical College of Virginia, Richmond, Virginia 23298

Polyglutamate derivatives of [³H]methotrexate (MTX) were detected in freshly isolated rat hepatocytes in suspension within 15 min after exposure to the folate analog. The rate of polyglutamate synthesis remained constant for at least one hr, and the polyglutamate derivatives accounted for an increasing proportion of the intracellular radiolabel with time. After initial exposure to 1 µM [³H]MTX, polyglutamate derivatives of MTX continued to be synthesized even after the extracellular [³H]MTX concentration had been reduced 20-fold. Prolonged exposure of hepatocytes in primary culture to 1 µM [³H]MTX resulted in the formation of longer-chain polyglutamate derivatives of MTX. The present studies demonstrate another important biosynthetic capacity of the freshly isolated hepatocyte and suggest the usefulness of this system for studying the mechanism of, and controlling factors in, the synthesis of polyglutamate derivatives of MTX. The ramifications of the formation of MTX polyglutamates on drug cytotoxicity in general and hepatotoxicity in particular are considered.

¹ Supported by NIH Grants CA-16906 and AM-18796.

² Supported by NIH Training Grant HL-07110.

³ To whom requests for reprints should be addressed.

Received 12/19/78. Accepted 4/18/79.

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