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The effect of chemical mutagens on purine and pyrimidine nucleotide biosynthesis

E Volkin, M E Boling, W H Lee

    Biochimica Et Biophysica Acta
    |January 25, 1983
    PubMed

    Insights

    Chemical mutagens significantly alter nucleotide biosynthesis in Novikoff hepatoma cells, increasing nucleotide pools while inhibiting key synthesis pathways. This suggests nucleotide metabolism is a potential target for mutagens.

    Area of Science:

    • Biochemistry
    • Molecular Biology
    • Cancer Research

    Background:

    • Chemical mutagens induce DNA damage through various mechanisms.
    • Understanding the broader cellular impact of mutagens is crucial for cancer research.

    Purpose of the Study:

    • To investigate the effects of chemical mutagens on nucleotide biosynthesis in Novikoff hepatoma cells.
    • To determine if nucleotide metabolism is a potential biochemical target of chemical mutagens.

    Main Methods:

    • Treatment of Novikoff hepatoma cells with various chemical mutagens (N-methyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide, 9-aminoacridine, mitomycin C).
    • Analysis of nucleoside triphosphate pool levels.
    • Assessment of de novo and salvage synthesis pathways for nucleotides using labeled precursors.
    • Measurement of RNA labeling to determine precursor incorporation.

    Main Results:

    • Mutagens caused a significant increase in all four nucleoside triphosphate pools.
    • Key synthetic pathways (CTP from uridine, GTP/ATP from hypoxanthine) were inhibited.
    • Direct phosphorylation of uridine and adenosine was relatively unaffected.
    • Increased nucleotide pools could not be explained by enhanced de novo synthesis.
    • Mutagens induced differential labeling of RNA nucleosides, linked to altered triphosphate precursor specific activities.

    Conclusions:

    • Chemical mutagens profoundly affect nucleotide biosynthesis in Novikoff hepatoma cells.
    • Nucleotide metabolism represents a significant biochemical target for chemical mutagens, beyond direct DNA interactions.
    • These findings highlight a novel mechanism of mutagenic action impacting cellular nucleotide pools.

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