Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse.
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.
Noda
Shuhei
S
Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Harada
Nobuhiko
N
Hida
Azumi
A
Fujii-Kuriyama
Yoshiaki
Y
Motohashi
Hozumi
H
Yamamoto
Masayuki
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002273:Carcinogens; D002384:Catalysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D008024:Ligands; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008956:Models, Chemical; D009154:Mutation; D051267:NF-E2-Related Factor 2; D010634:Phenobarbital / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*
D000975:Antioxidants; D002273:Carcinogens; D004268:DNA-Binding Proteins; D008024:Ligands; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D018336:Receptors, Aryl Hydrocarbon; D015534:Trans-Activators; D002083:Butylated Hydroxyanisole; D008748:Methylcholanthrene; D010634:Phenobarbital