Estradiol disrupts constitutive androstane receptor (CAR)-mediated bile acid homeostasis in a murine model of intrahepatic cholestasis of pregnancy (ICP), and this effect is reversed by CAR ligands

Estrogens impair bile acid (BA) homeostasis, leading to intrahepatic cholestasis of pregnancy (ICP). ICP is characterized by elevated serum bilirubin and BAs, severe pruritus, and an increased risk of adverse perinatal outcomes. The constitutive androstane receptor (CAR) regulates genes involved in xenobiotic and BA detoxification. Previous studies suggest that CAR activation is protective in bile duct ligation–induced cholestasis and that major genes involved in BA elimination are downregulated in ethinylestradiol (EE)–induced cholestasis in mice. We examined whether CAR ligands could ameliorate cholestasis and prevent hepatic injury in an EE-induced cholestasis model using biochemical, transcriptomic, and BA metabolomic analyses. We found that estradiol inhibits and downregulates CAR target genes in vitro. Consistently, EE significantly suppresses hepatic CAR target gene expression in vivo, whereas the murine CAR agonist TCPOBOP partially restores the expression of selected detoxification genes, improves plasma alkaline phosphatase levels, and decreases hepatic BA accumulation. In humanized PXR–CAR–CYP3A mice with EE-induced cholestasis, MI763F, a novel and potent human CAR agonist, recapitulates the effects of TCPOBOP on key genes involved in BA metabolism and the BA metabolome, and significantly reduces hepatic BA accumulation. These results demonstrate that CAR ligands counteract EE-mediated disruption of genes involved in BA homeostasis.