Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P450 3A4 in human hepatocytes

Abstract

Cytochrome P450 3A4 (CYP 3A4) is the most abundant cytochrome P450 enzyme in human liver and metabolizes more than 60% of prescribed drugs in human body. Patients with liver conditions such as cirrhosis show increased secretion of cytokines (e.g, interleukin-6) and decreased capacity of oxidation of many drugs. In this study, we provided molecular evidence that cytokine secretion directly contributed to the decreased capacity of oxidative biotransformation in human liver. After human hepatocytes were treated with IL-6, the expression of CYP3A4 decreased at both mRNA and protein levels, so did the CYP3A4 enzymatic activity. Meanwhile, the repression of CYP3A4 by IL-6 occurred after the decrease of pregnane X receptor (PXR) in human hepatocytes. The PXR-overexpressed cells (transfected with human PXR) increased the CYP3A4 mRNA level, and the repression of CYP3A4 by IL-6 was greater in the PXR-overexpressed cells than in the control cells. Further, PXR-knockdown (transfected with siPXR construct) decreased the CYP3A4 mRNA level with less repression by IL-6 than in the control cells transfected with corresponding vector. Collectively, our study suggests that PXR is necessary for IL-6-mediated repression of the CYP3A4 expression in human hepatocytes.

Effects of Interleukin-6 (IL-6) and an Anti-IL-6 Monoclonal Antibody on Drug-Metabolizing Enzymes in Human Hepatocyte Culture

“…This study expands on previous studies exploring IL-6 regulation of cytochrome P450 enzymes in human hepatocyte culture (Aitken and Morgan, 2007;Lee et al, 2009;Yang et al, 2010). In part because of regulatory interest, dissecting out the components of the APR is of industrial interest, because companies working on an anticytokine drug want to know whether their cytokine alone elicits this effect on cytochromes P450.…”

Pregnane X Receptor Is SUMOylated to Repress the Inflammatory Response

“…Disruption of the molecular interaction between PXR and DNA through increased protein-protein interaction between the p65 subunit of NF-B and retinoid X receptor has been proposed as the molecular basis for transrepression of the xenobiotic response by inflammatory cytokines (Gu et al, 2006), although the precise mechanism that gives rise to the selective interaction between these two proteins is not currently known. Several studies indicate that PXR-mediated inhibition of NF-B is required for antifibrogenic effects and repression of CYP3A4 expression in hepatocytes (Axon et al, 2008;Yang et al, 2010). Further research will be necessary to elucidate the biochemical details of this response; however, the data presented here provide a stable platform for launching these important studies.…”

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

“…Rifampicin acts on PXR, the nuclear receptor that controls the bulk of CYP3A4 transcription (Li and Chiang, 2006). PXR is the same receptor acted upon by IL-6 signaling (Yang et al, 2010), and rifampicin has been previously used to augment the effects of inflammatory agents on CYP3A4 in hepatocytes (Pascussi et al, 2000;Gu et al, 2006).…”