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Murine alpha/beta interferons inhibit benzo(a)pyrene activation and mutagenesis in mice
Abstract:
In addition to their antiviral and immune regulatory properties, interferons (IFNs) are known to depress hepatic cytochrome P450-dependent metabolism. As many chemical mutagens and carcinogens require bioactivation by the mixed-function monooxygenase (MFO) system in order to be genotoxic, a combined genetic and biochemical approach was used to establish whether IFNs could inhibit the activation of benzo(a)pyrene (BaP) to the ultimate clastogenic metabolite(s) in vivo. Treatment of mice with murine IFN-alpha/beta depressed cytochrome P450 content, as well as ethoxyresorufin O-deethylase activity (EROD), as a probe of class IA1 P450 isozymes, for 24 hrs and delayed the attainment of normal levels to approximately 30 hrs. After IFNs plus BaP treatment, EROD activity showed a reduction up to 70% after 24 hrs with an enhancement in activity at 30 hrs. A positive correlation exists between the rate of inhibition of oxidative BaP hepatic metabolism and inhibition of clastogenic effects in vivo, as scored in the bone marrow chromosome aberration assay.
Insights
Interferons (IFNs) inhibit the metabolism of benzo(a)pyrene (BaP) in mice, reducing its activation into harmful compounds. This finding suggests IFNs may decrease the genotoxic effects of certain environmental carcinogens.
Area of Science:
- Biochemistry
- Toxicology
- Immunology
Background:
- Interferons (IFNs) possess antiviral and immune regulatory functions.
- IFNs are known to suppress hepatic cytochrome P450-dependent metabolism.
- Cytochrome P450 enzymes, particularly the mixed-function monooxygenase (MFO) system, are crucial for bioactivating chemical mutagens and carcinogens.
Purpose of the Study:
- To investigate whether interferons (IFNs) can inhibit the in vivo bioactivation of benzo(a)pyrene (BaP) to its genotoxic metabolites.
- To establish a link between the inhibition of BaP hepatic metabolism and its clastogenic effects.
Main Methods:
- A combined genetic and biochemical approach was employed in mice.
- Murine IFN-alpha/beta treatment was administered.
- Hepatic cytochrome P450 content and ethoxyresorufin O-deethylase (EROD) activity were measured.
- Bone marrow chromosome aberration assay was used to assess clastogenic effects.
Main Results:
- IFN-alpha/beta treatment depressed cytochrome P450 content and EROD activity for 24 hours, with delayed normalization around 30 hours.
- Following combined IFN and BaP treatment, EROD activity decreased by up to 70% at 24 hours, with a subsequent increase at 30 hours.
- A positive correlation was observed between the inhibition rate of BaP hepatic metabolism and the reduction in clastogenic effects.
Conclusions:
- Interferons (IFNs) inhibit the metabolic activation of benzo(a)pyrene (BaP) in vivo.
- The observed inhibition of BaP metabolism by IFNs correlates with a decrease in their clastogenic potential.
- These findings suggest a potential role for IFNs in modulating the genotoxicity of certain environmental carcinogens.