Porcine interleukin-6 enhances the expression of CYP2C33 through a constitutive androstane receptor/retinoid X receptor-mediated pathway

Abstract

1. Cytochrome P450, which is expressed in humans and other animals, is a superfamily of drug-metabolizing enzymes that play important roles in the metabolism of endogenous and xenobiotic substrates via oxidation, peroxidation and reduction. Of endogenous substrates, interleukin (IL)-6 is a crucial cytokine involved in inflammation in the liver. The present study aims to elucidate the mechanisms through which IL-6 modulates cytochrome P450 expression.

2. CYP2C33 expression was found to be increased in HepLi cells and primary porcine hepatocytes treated with IL-6 in a concentration-dependent manner. IL-6 treatment also increased the expression of the transcriptional regulators, constitutive androstane receptor (CAR) and pregnane X receptor.

3. Overexpression of CAR promoted CYP2C33 expression at the mRNA and protein levels, whereas knockdown of CAR by small interfering RNA reduced CYP2C33 expression. Luciferase assays showed that IL-6 treatment of HepLi cells and primary porcine hepatocytes increased CYP2C33 promoter activity. Co-immunoprecipitation and western blotting demonstrated that CAR and RXR could form heterodimers.

4. IL-6 affects CYP2C33 expression through CAR/retinoid X receptor (RXR) heterodimers.

Keywords:

• Drug-metabolizing enzymes
• CYP2C33
• hepatocytes
• interleukin-6
• constitutive androstane receptor

Acknowledgement

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

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Natural Science Foundation of China [No. 31101794], the National Key Research and Development Program of China [2017YFD0501000] and the Major Program of Hubei Science & Technology Innovation [No. 2015ABA041].