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Uptake and Metabolism of N⁵-Formyltetrahydrofolate by L1210 Leukemia Cells¹

Departments of Pharmacology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510

N⁵-Formyltetrahydrofolate was accumulated by L1210 cells by a temperature-dependent process. Accumulation of intracellular radioactivity was inhibited by p-chloromercuribenzoate, iodoacetate, fluoride ion, and ouabain. The rate of influx of N⁵-formyltetrahydrofolate was decreased by the presence of methotrexate (MTX) or 5-methyltetrahydrofolate but by only high concentrations of folic acid. Radiolabel, accumulated by the L1210 cells from radiolabeled 5-formyltetrahydrofolate (f-FH₄), was displaced by 5-methyltetrahydrofolate and MTX. No significant displacement of radioactivity was obtained when folic acid was tested at similar concentrations. Chromatography of accumulated intracellular radiolabels after incubation of the cells with radiolabeled f-FH₄ demonstrated that the latter was metabolized rapidly to other folate coenzymes. The efflux of MTX was increased by the addition of f-FH₄ to the media.

These findings suggest that f-FH₄ transport into the L1210 cells is carrier mediated and that the cellular metabolism of this compound is rapid. This carrier system appears to be utilized also by MTX and 5-methyltetrahydrofolate and, to a lesser extent, by folic acid. Additional mechanisms by which f-FH₄ reverses the action of MTX (namely, competition for uptake and enhancement of MTX efflux) are suggested by these studies.

¹ This work was supported by USPHS Grants CA-08010 and CA-08341 and by Grant T-403 from the American Cancer Society.

² Postdoctoral fellow of the USPHS (PHS CA-05012). Present address: Department of Biochemistry, University of Rochester School of Medicine, Rochester, N. Y.

³ Merck, Sharp and Dohme International Fellow in Clinical Pharmacology. Present address: Department of Biochemistry, John Curtin School of Medical Research, Australian National University, Canberra City, Australia.

⁴ Career Development Awardee of the National Cancer Institute (5-K3-CA-8853).

Received 8/18/71. Accepted 3/23/72.