[[Inflammation and drug metabolism: NF-kappB and the CAR and PXR xeno-receptors].
Decreased drug metabolism, hyperbilirubinemia and intrahepatic cholestasis are frequently observed during inflammation. Additionally, it has long been appreciated that exposure to drug metabolism-inducing xenobiotics can impair immune function. The nuclear receptor CAR (constitutive androstane receptor or NR1I3) and PXR (pregnane X receptor, NR1I2) control phase I (cytochrome P450 2B and 3A), phase II (GSTA, UGT1A1), and transporter (MDR1, SLC21A6, MRP2) genes involved in drugs metabolism, bile acids and bilirubin clearance in response to xenobiotics. It is well known that inflammation, through the activation of NF-kappaB pathway, leads to a decrease of CAR, PXR and RXRalpha expression and the expression of their target genes. In addition, a new study reveals the mutual repression between PXR and NF-kappaB signaling pathways, providing a molecular mechanism linking xenobiotic metabolism and inflammation.
Pascussi
Jean-Marc
JM
Inserm, U632, Montpellier, France. pascussi@montp.inserm.fr
Vilarem
Marie-José
MJ
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism; D001711:Biotransformation / Q000502:physiology*; D000090702:Constitutive Androstane Receptor; D016207:Cytokines / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology; D008658:Inactivation, Metabolic / Q000502:physiology; D007239:Infections / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D015262:Xenobiotics / Q000493:pharmacokinetics*
D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; C000625853:Nr1i2 protein, mouse; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015262:Xenobiotics; D001663:Bilirubin