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Effects of genetically different strains of mice on the microsomal activation of 2-aminofluorene

J Bender, R Razdan, J R Lumb

    Toxicology Letters
    |September 1, 1982
    PubMed

    Insights

    Mice strains susceptible to chemical-induced cancer exhibit higher cytochrome P450 (Cyt P450) activity and activate 2-aminofluorene (2-AF) to mutagenic forms more readily than strains prone to spontaneous tumors.

    Area of Science:

    • Biochemistry
    • Toxicology
    • Genetics

    Background:

    • Cytochrome P450 (Cyt P450) enzymes are crucial for metabolizing xenobiotics, including environmental carcinogens.
    • Inter-strain variations in Cyt P450 activity can influence an organism's susceptibility to chemical-induced carcinogenesis.
    • 2-aminofluorene (2-AF) is a model compound used to assess metabolic activation to mutagenic intermediates.

    Purpose of the Study:

    • To investigate the relationship between mouse strain, microsomal cytochrome P450 (Cyt P450) activity, and the metabolic activation of 2-aminofluorene (2-AF).
    • To compare Cyt P450 activity and 2-AF mutagenicity between mouse strains with differing susceptibilities to chemical carcinogenesis and spontaneous tumors.

    Main Methods:

    • Assessed basal and induced microsomal Cyt P450 activity in five different mouse strains.
    • Measured the ability of microsomal preparations to activate 2-aminofluorene (2-AF) to its mutagenic form.
    • Utilized Aroclor 1254 to induce hepatic microsomes and evaluate its effect on Cyt P450 activity and 2-AF metabolism.

    Main Results:

    • Mice strains susceptible to chemical carcinogenesis (Group A: C57BL/6J, BALB/cJ) displayed higher basal Cyt P450 levels compared to strains prone to spontaneous tumors (Group B: CE/J, A/HeJ, C3H/HeJ).
    • Group A strains demonstrated significantly increased activation of 2-AF to mutagenic metabolites.
    • Induction with Aroclor 1254 amplified the observed differences in Cyt P450 activity and 2-AF mutagenicity between the two groups.

    Conclusions:

    • Genetic background significantly influences Cyt P450 activity and the capacity to metabolize xenobiotics like 2-AF.
    • Higher Cyt P450 activity in susceptible strains correlates with enhanced metabolic activation of pro-carcinogens, potentially explaining differential carcinogenesis.
    • Cyt P450 induction further accentuates these strain-specific metabolic differences, highlighting their importance in toxicological responses.

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