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

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-gamma-mediated CYP3A29 expression in pig liver microsomes, primary porcine hepatocytes, and a cultured hepatocyte cell line. 2. IFN-gamma significantly up-regulated CYP3A29 and PXR expressions at mRNA and protein levels in a dose-dependent manner. IFN-gamma treatment significantly increased the metabolism of nifedipine. PXR and IFN-gamma 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-gamma-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-gamma on CYP3A29 expression is mediated via PXR.