Background: Nuclear receptor are major regulators of hepatic drug metabolizing enzymes and antioxidants enzymes. Nuclear receptor humanized mice were used for overcome species differences between experimental animals and human. Objective: The present study was performed to investigate the hepatic regulation of antioxidant enzymes in pregnane X receptor (PXR) and constitutive androstane receptor (CAR) double humanized mice treated with the human PXR ligand, rifampicin (RIF; 10 mg/kg for 4 days). Results: RIF decreased the hepatic protein levels of superoxide dismutase-1, thioredoxin-1, and γ-glutamylcysteine ligase catalytic subunit in wild-type (WT) mice, but not in the double humanized mice. Catalase protein levels were decreased by RIF in both WT and double humanized mice. The hepatic protein level and activity of glutathione reductase (GR) were increased in the humanized mice treated with RIF, but decreased in WT mice. Glutathione S-transferase (GST) alpha-class (GSTA) and mu-class (GSTM) but not pi-class were induced by RIF in the humanized mice, but not in WT mice. The activities of total GST, GSTA and GSTM were also increased only in humanized mice treated with RIF. Conclusion: These results suggest that PXR and CAR may play roles in xenobiotic-induced hepatic regulation of GSTA, GSTM, and GR. The PXR/CAR double humanized mouse can be used as a suitable predictive model of the regulation of human antioxidant enzymes by xenobiotics.
Bibliographical noteFunding Information:
This research was supported by a National Research Foundation of Korea Grant funded by the Korean Government (2018M3A9H1021640 and 2021R1A2C2004696) and Korea Institute of Science and Technology Europe basic research program (Project no. 12001).
© 2021, The Korean Society of Toxicogenomics and Toxicoproteomics.
- Glutathione S-transferase
- Glutathione reductase
- Humanized mice
- Nuclear receptor
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Pharmacology, Toxicology and Pharmaceutics(all)
- Public Health, Environmental and Occupational Health
- Health, Toxicology and Mutagenesis