Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis. Mus musculus

The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital (PB) on gene transcription. To investigate the relative role of CAR and PXR in the induction response, cDNA arrays were generated containing 120 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 PB for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments unexpectedly revealed that if CAR and PXR are deleted, PB increases the expression of several other nuclear receptors and genes involved in drug metabolism and cholesterol biosynthesis. Overall design: Animals were injected i.p. 100mg/kg phenobarbital 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 phenobarbital treated ones and hybridized to Sterolgene V1 arrays.