T0901317, a potent LXR agonist, is an inverse agonist of CAR

The basal transcriptional activity of unliganded human constitutive androstane receptor (hCAR) was shown to be repressed by the potent liver X receptor (LXR) agonist, T0901317, in a concentration-dependent manner using a reporter assay in cultured cells. T0901317 also repressed the basal transcriptional activity of both mouse and rat CAR. The certified hCAR agonist, CITCO, partially reversed this repressive effect of T0901317 on hCAR basal activity. Unlike hCAR, a three alanine insertion mutant and the splice variant 2 of hCAR require agonists, such as CITCO, to become transcriptionally active and the CITCO-induced reporter activity was repressed by T0901317. As has been previously shown for the typical hCAR inverse agonist, PK11195, T0901317 blocked the interaction of hCAR with steroid receptor co-activator 1 (SRC1). In contrast, the interaction between hCAR and nuclear receptor corepressor 1 (NCoR1) was promoted by PK11195 and T0901317. Furthermore, the hCAR-mediated basal induction of endogenous cytochrome P450 2B6 (CYP2B6) mRNA was adversely affected by co-treatment with T0901317.