Résumé
During the inflammatory response, intrahepatic cholestasis and decreased drug metabolism are frequently observed. At the hepatic level, the orphan nuclear constitutive androstane receptor (CAR) (NR1I3) controls phase I (cytochrome P450 [CYP] 2B and CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance in response to xenobiotics such as phenobarbital or endobiotics such as phenobarbital or endobiotics such as bilirubin. We investigated the negative regulation of CAR, a glucocorticoid‐responsive gene, via proinflammatory cytokine interleukin 1β (IL‐1β) and lipopolysaccharides (LPSs) in human hepatocytes. We show that IL‐1β decreases CAR expression and decreases phenobarbital‐ or bilirubin‐mediated induction of CYP2B6, CYP2C9, CYP3A4, UGT1A1, GSTA1, GSTA2, and SLC21A6 messenger RNA. This occurs via nuclear factor kB (NF‐kB) p65 activation, which interferes with the enhancer function of the distal glucocorticoid response element that we have identified recently in the CAR promoter. We demostrate that: (1) LPSs, IL‐1β, or overexpression of p65Re1A inhibit glucocorticoid receptor (GR)‐mediated CAR transactivation; (2) these suppressive effects can be blocked both by pyrrolidine dithiocarbamate, an inhibitor of NF‐kB activation, or by overexpression of SRIkBα, a NF‐kB repressor; and (3)the GR agonist dexamethasone induces histone H4 acetylation at the proximal CAR promoter region, whereas LPSs and IL‐1β inhibit this acetylation as assessed via chromatin immunoprecipitation assay. In conclusion, GR/NF‐kB interaction affects CAR gene transcription through chromatin remodeling and provide a mechanistic explanation for the long‐standing observation that inflammation and sepsis inhibit drug metabolism while inducing intrahepatic cholestasis or hyperbilirubinemia. Supplementary material for this article can be found on the Hepatology website (http:/interscience.wiley.com/jpages/0270–9139/suppmat/index.html). (Hepatology 2004;40:951‐960).