The covalent binding of bromobenzene with nucleic acids

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Published on: April 26, 2013

A Colacci, G Arfellini, M Mazzullo

    Toxicologic Pathology
    |January 1, 1985
    PubMed

    Insights

    Hepatotoxic bromobenzene binds to DNA and proteins in rat and mouse liver and kidney. This covalent binding, mediated by a P-450 enzyme system, suggests potential genotoxic carcinogenicity.

    Area of Science:

    • Toxicology
    • Biochemistry
    • Carcinogenesis

    Background:

    • Hepatotoxic compounds can exert toxicity through covalent binding to cellular macromolecules.
    • Bromobenzene is a known hepatotoxic agent, but its interaction with DNA and the mechanisms involved require further elucidation.

    Purpose of the Study:

    • To investigate the in vivo and in vitro binding of bromobenzene to DNA, RNA, and proteins.
    • To identify the enzymatic systems responsible for bromobenzene bioactivation.
    • To assess the potential genotoxic mechanisms underlying bromobenzene's carcinogenicity.

    Main Methods:

    • In vivo and in vitro covalent binding assays using radiolabeled bromobenzene.
    • Analysis of binding in liver, kidney, and lung tissues of rats and mice.
    • Enzymatic bioactivation studies using liver microsomes and specific enzyme inhibitors (SKF 525-A) and inducers (phenobarbitone).
    • Photoactivation studies using ultraviolet light.

    Main Results:

    • Bromobenzene demonstrated significant covalent binding to DNA, RNA, and proteins in rat and mouse liver, and to a lesser extent in mouse kidney.
    • Enzyme-mediated bioactivation occurred primarily via a P-450 dependent-microsomal mixed-function oxidase system, particularly in liver and lung microsomes.
    • Poly(G) and poly(A) were the most reactive synthetic polynucleotides.
    • Ultraviolet light also induced DNA-reactive forms of bromobenzene.

    Conclusions:

    • Bromobenzene's covalent binding to macromolecules, especially DNA, is mediated by a P-450 system, indicating a potential genotoxic mechanism for its carcinogenicity.
    • The covalent binding index (CBI) suggests bromobenzene may be a moderately oncogenic substance.
    • Both metabolic and photoactivation pathways contribute to bromobenzene's DNA-reactive potential.

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