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Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse
Shuhei Noda1, Nobuhiko Harada, Azumi Hida
1Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Abstract:
The arylhydrocarbon receptor (AhR) regulates the expression of cytochrome P450 (CYP)-1 gene family members which catalyze xenobiotic Phase I metabolism, while Nrf2 exerts the concerted regulation of Phase II enzyme genes. We generated AhR and Nrf2 compound null mutant mice to examine the integrated function of AhR- and Nrf2-regulated enzymes in detoxification. Furthermore, we used this mouse model, by administering three different classes of chemical inducers, to examine how xenobiotic metabolism may be influenced in the absence of signals transduced by AhR or Nrf2. The compound mutant mice responded only weakly to AhR ligand or Phase II inducer, while they displayed a clear response to phenobarbital, an inducer of the CYP2B family through another, unrelated transcription factor. Here, we report an initial characterization of the AhR-Nrf2 double mutant mice, which may serve as a simplified bioassay system to evaluate xenobiotic toxicity and metabolic biotransformation of various drugs and environmental chemicals.
Insights
We created double mutant mice lacking aryl hydrocarbon receptor (AhR) and Nrf2 to study detoxification. These mice show altered responses to chemical inducers, suggesting a simplified system for evaluating xenobiotic metabolism and toxicity.
Area of Science:
- Biochemistry
- Toxicology
- Genetics
Background:
- The aryl hydrocarbon receptor (AhR) and Nrf2 are key regulators of xenobiotic metabolism.
- AhR controls Phase I (CYP) enzymes, while Nrf2 regulates Phase II detoxification enzymes.
Purpose of the Study:
- To investigate the integrated function of AhR- and Nrf2-regulated enzymes in detoxification.
- To characterize a novel compound null mutant mouse model for studying xenobiotic metabolism.
Main Methods:
- Generation of AhR and Nrf2 compound null mutant mice.
- Administration of three classes of chemical inducers (AhR ligand, Phase II inducer, phenobarbital).
- Analysis of the response of mutant mice to chemical induction.
Main Results:
- Compound mutant mice exhibited weak responses to AhR ligands and Phase II inducers.
- A clear response was observed with phenobarbital, an inducer of CYP2B via a separate pathway.
- The study provides initial characterization of AhR-Nrf2 double mutant mice.
Conclusions:
- AhR and Nrf2 play crucial roles in the coordinated regulation of xenobiotic detoxification.
- The AhR-Nrf2 double mutant mouse model offers a simplified system for evaluating xenobiotic toxicity.
- This model can aid in assessing the metabolic biotransformation of drugs and environmental chemicals.