IFN-γ regulates cytochrome 3A29 through pregnane X receptor in pigs

Abstract

1. The expression and the activity of cytochromes P450 (CYPs) can be elevated by the activation of nuclear receptors. The pregnane X receptor (PXR, or nuclear receptor NR1I2) is a ligand-activated transcription factor that mediates responses to diverse xenobiotics and endogenous chemicals. Here we investigated the regulatory role of PXR in IFN-γ-mediated CYP3A29 expression in pig liver microsomes, primary porcine hepatocytes, and a cultured hepatocyte cell line.

2. IFN-γ significantly up-regulated CYP3A29 and PXR expressions at mRNA and protein levels in a dose-dependent manner. IFN-γ treatment significantly increased the metabolism of nifedipine. PXR and IFN-γ treatments significantly enhanced the activity of CYP3A29 promoter and the upstream region from −1473 to −1021 of CYP3A29 might be PXR-binding site. Moreover, the IFN-γ-induced CYP3A29 expression was blocked by PXR knockdown, whereas CYP3A29 mRNA and protein expression levels were dramatically elevated by PXR overexpression.

3. The regulatory effect of IFN-γ on CYP3A29 expression is mediated via PXR.

• Cytochrome P450
• CYP3A29
• interferon-γ
• pig
• pregnane X receptor

Acknowledgements

The authors would like to thank Drs. Lanjuan Li and Xiaopin Pan from Zhejiang University for providing the Hep-Li cell line.

Declaration of interest

This work was supported by the Natural Science Foundation of China (No. 31101794) and the Fundamental Research Fund for Central Universities (No. 2009QC007).