Biodisposition of theophylline. II. Effect of aromatic hydrocarbon treatment in mice

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C J Betlach, T N Tozer

    Drug Metabolism and Disposition: the Biological Fate of Chemicals
    |July 1, 1980
    PubMed

    Insights

    Polycyclic aromatic hydrocarbons significantly alter theophylline clearance in mice. Genetic variations in mouse strains influence the metabolic response to these compounds, affecting drug metabolism pathways.

    Area of Science:

    • Pharmacology and Toxicology
    • Genetics and Genomics
    • Drug Metabolism

    Background:

    • Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants known to affect drug metabolism.
    • Theophylline is a drug commonly metabolized via hepatic pathways.
    • Genetic variability among inbred mouse strains can influence drug response and metabolic enzyme activity.

    Purpose of the Study:

    • To investigate the impact of polycyclic aromatic hydrocarbons (PAHs) on theophylline clearance across different inbred mouse strains.
    • To identify genetic factors contributing to differential responses in drug metabolism.
    • To elucidate the specific metabolic pathways involved in PAH-induced changes in theophylline metabolism.

    Main Methods:

    • Administration of polycyclic aromatic hydrocarbons to six inbred mouse strains.
    • Measurement of theophylline clearance rates in treated and control mice.
    • Analysis of metabolic byproducts, including 1,3-dimethyluric acid, to assess pathway activity.

    Main Results:

    • Significant differences in theophylline clearance were observed among the six inbred mouse strains following PAH exposure.
    • DBA/2 and SJL strains exhibited non-responsiveness, while C3H/HeJ, C57BL/6, BALB/c, and A/J strains showed responsiveness.
    • Responsive strains demonstrated a 2.3 to 3.4 fold increase in total body clearance, linked to general metabolic pathway induction, with variations attributed to 1,3-dimethyluric acid oxidation.

    Conclusions:

    • Inbred mouse strain genetics play a crucial role in determining the response to polycyclic aromatic hydrocarbons regarding theophylline metabolism.
    • The induction of metabolic pathways by PAHs is variable and strain-dependent.
    • Oxidation to 1,3-dimethyluric acid is a key factor in the observed variations in PAH-induced theophylline clearance.

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