Effect of TCPOBOP on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis

The nuclear receptor CAR (constitutive androstane receptor) mediates the effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on gene transcription. To investigate the relative role of CAR and also PXR in the induction response, cDNA arrays were generated containing 120 (Sterolgene V1) genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with TCPOBOP for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments show the complex role of CAR receptor in the expression of genes involved in drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 10mg/kg TCPOBOP or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the TCPOBOP treated ones and hybridized to Sterolgene V1 arrays.