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Journal of Pharmacology and Experimental Therapeutics

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OtherCHEMOTHERAPY/GENE THERAPY

Folate Depletion Induced by Methotrexate Affects Methionine Synthase Activity and Its Susceptibility to Inactivation by Nitrous Oxide

Torunn Fiskerstrand, Per Magne Uel and and Helga Refsum
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1305-1311;
Torunn Fiskerstrand
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Per Magne Uel
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and Helga Refsum
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Abstract

We compared the effects of methotrexate (MTX) and nitrous oxide on the methionine (Met) synthase system in two variants of a human glioma cell line. The cells were protected from cytotoxic effect of MTX by adding thymidine and hypoxanthine to the cell culture medium. MTX (0–1 μM) was associated with a dose- and time-dependent reduction in 5-methyltetrahydrofolate (5-methyl-THF) in both cell lines. Already after 3 hr of exposure, 5-methyl-THF was reduced by 50% and after additional 48 hr, the level was undetectable. In addition to reduction in folate level, homocysteine (Hcy) remethylation in intact cells was markedly inhibited as judged by an increased export of Hcy from the cells, and Met synthase activity in cell extracts and level of cellular methylcobalamin (CH3Cbl) declined. MTX reduced Hcy remethylation and CH3Cbl level more efficiently than nitrous oxide. In both cell variants, the inactivation of Met synthase by nitrous oxide was almost completely prevented in cells pre-exposed to MTX. This indicates that there is no catalytic turnover in cells exposed to MTX, and emphasizes the importance of the sequence of administration for synergistic effect of this drug combination. In conclusion, our data show that MTX through depletion of 5-methyl-THF reduces both the Met synthase activity and the cellular CH3Cbl level. Moreover, the effect of MTX on the Hcy remethylation is more pronounced than the inhibition caused by nitrous oxide. These observations should be taken into account in studies on MTX pharmacodynamics.

Footnotes

  • Send reprint requests to: Dr. Torunn Fiskerstrand Department of Pharmacology, Armauer Hansens hus, University of Bergen, N-5021 Bergen, Norway.

  • ↵1 This work was supported by grants from the Norwegian Cancer Society and the Norwegian Research Council.

  • Abbreviations:
    MTX
    methotrexate
    Met
    methionine
    THF
    tetrahydrofolate
    Hcy
    homocysteine
    Cbl
    cobalamin
    Thd
    thymidine
    Hx
    hypoxanthine
    DMEM
    Dulbecco’s modified Eagle’s medium
    PBS
    phosphate-buffered saline
    HPLC
    high-performance liquid chromatography
    • Received October 4, 1996.
    • Accepted May 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherCHEMOTHERAPY/GENE THERAPY

Folate Depletion Induced by Methotrexate Affects Methionine Synthase Activity and Its Susceptibility to Inactivation by Nitrous Oxide

Torunn Fiskerstrand, Per Magne Uel and and Helga Refsum
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1305-1311;

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OtherCHEMOTHERAPY/GENE THERAPY

Folate Depletion Induced by Methotrexate Affects Methionine Synthase Activity and Its Susceptibility to Inactivation by Nitrous Oxide

Torunn Fiskerstrand, Per Magne Uel and and Helga Refsum
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1305-1311;
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