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

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.