Effects of rifampicin on hepatic antioxidant enzymes in PXR and CAR double humanized mice

• Published in: Molecular & cellular toxicology Vol. 17; no. 3; pp. 277 - 286
• Main Authors: Choi, Young Jae, Ryu, Chang Seon, Lee, Sang Yoon, Kim, Ha Gyeong, Kim, Nan Young, Lee, Ji-Yoon, Oh, Soo Jin, Park, Han-Jin, Cho, Seung-Woo, Kim, Jong-Hoon, Kim, Sang Kyum
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01-07-2021; Springer Nature B.V; 대한독성 유전단백체 학회
• Subjects: Antioxidants; Biomedical and Life Sciences; Catalase; Cell Biology; Enzymes; Glutathione reductase; Glutathione transferase; Life Sciences; Original Article; Pharmacology/Toxicology; Prediction models; Proteins; Rifampin; Superoxide dismutase; Thioredoxin; Xenobiotics; γ-Glutamylcysteine; 생물학; Nuclear receptor; Rifampicin; Humanized mice; transferase; Glutathione reductase; Glutathione
• ISSN: 1738-642X; 2092-8467
• DOI: 10.1007/s13273-021-00134-9

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.