RT Journal Article SR Electronic T1 Colchicine Down-Regulates Cytochrome P450 2B6, 2C8, 2C9, and 3A4 in Human Hepatocytes by Affecting Their Glucocorticoid Receptor-Mediated Regulation JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 160 OP 169 DO 10.1124/mol.64.1.160 VO 64 IS 1 A1 Dvor̆ák, Zdenĕk A1 Modrianský, Martin A1 Pichard-Garcia, Lydiane A1 Balaguer, Patrick A1 Vilarem, Marie-Jose A1 Ulrichová, Jitka A1 Maurel, Patrick A1 Pascussi, Jean-Marc YR 2003 UL http://molpharm.aspetjournals.org/content/64/1/160.abstract AB The xenobiotic-mediated induction of three major human liver cytochrome P450 genes, CYP2B6, CYP2C9, and CYP3A4, is known to be regulated by the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). CAR and PXR are regulated, at least in part, by the glucocorticoid receptor (GR) and the hypothesis of a signal transduction cascade GR-[CAR/PXR]-P450 has been proposed. This study was aimed at testing this hypothesis in primary human hepatocytes by using the tubulin network disrupting agent colchicine. Colchicine (COL) decreased both basal and rifampicin- and phenobarbital-inducible expression of CYP2B6, CYP2C8/9, and CYP3A4. A parallel down-regulation of mRNA expression of CAR, PXR, and tyrosine aminotransferase, a prototypic gene directly regulated by GR, was observed. COL affected neither the level of GR mRNA nor ligand binding to GR. To evaluate the effect of colchicine on GR-mediated gene transactivation, HeLa cells stably or transiently transfected with a GR-responsive element-dependent luciferase reporter gene were used. COL decreased the dexamethasone-induced luciferase expression in stably transfected cell line by 50%, whereas GR transactivation in transiently transfected cells was not affected by COL. In contrast, ligand-dependent GR translocation in the human embryonic kidney 293 cell line transiently transfected with GFP-GR was inhibited by COL. We conclude that alteration of the signal transduction mediated through the GR-[CAR/PXR]-P450 cascade by colchicine is responsible for the down-regulation of CYP2C9 and CYP3A4, implicating cytoskeleton as necessary for correct functioning of this cascade under physiological conditions.