Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance.
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 bilirubin. We investigated the negative regulation of CAR, a glucocorticoid-responsive gene, via proinflammatory cytokine interleukin 1beta (IL-1beta) and lipopolysaccharides (LPSs) in human hepatocytes. We show that IL-1beta 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 kappaB (NF-kappaB) p65 activation, which interferes with the enhancer function of the distal glucocorticoid response element that we have identified recently in the CAR promoter. We demonstrate that: (1) LPSs, IL-1beta, or overexpression of p65RelA inhibit glucocorticoid receptor (GR)-mediated CAR transactivation; (2) these suppressive effects can be blocked both by pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, or by overexpression of SRIkBalpha, a NF-kappaB repressor; and (3) the GR agonist dexamethasone induces histone H4 acetylation at the proximal CAR promoter region, whereas LPSs and IL-1beta inhibit this acetylation as assessed via chromatin immunoprecipitation assay. In conclusion, GR/NF-kappaB 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.
Assenat
Eric
E
Service de Chirurgie Digestive, Hôpital Saint Eloi, Montpellier, France.
Gerbal-Chaloin
Sabine
S
Larrey
Dominique
D
Saric
Jean
J
Fabre
Jean-Michel
JM
Maurel
Patrick
P
Vilarem
Marie-José
MJ
Pascussi
Jean Marc
JM
D000107:Acetylation; D001663:Bilirubin / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D000090702:Constitutive Androstane Receptor; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006367:HeLa Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010599:Pharmacokinetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D005938:Glucocorticoids; D006657:Histones; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000716327:NR1I3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D014157:Transcription Factors; D001663:Bilirubin