Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes

The marked impairment of hepatic drug metabolism during inflammation and in fections has been known for many years and shown to result from downregulat ion of cytochrome P450s (CMP) by cytokines, However, the mechanism of this repression is unknown. Using primary cultures of human hepatocytes, we show here that interleukin-6 (IL-6) rapidly and markedly decreases the expressi on of PXR (pregnane X receptor) and CAR (constitutively activated receptor) mRNAs, but does not affect the levels of dioxin receptor and glucocorticoi d receptor mRNA, In parallel, IL-6 decreases both rifampicin- and phenobarb ital-mediated induction of CYP2B6, CYP2C8, CYP2C9, and CYP3A4. As the trans criptional activity of PXR and CAR is not affected by IL-6 in cell-based re porter assays, our data suggest that the loss of CYP2 and CYP3 inducibility results from the negative regulation of PXR and CAR gene expression by thi s cytokine. (C) 2000 Academic Press.