Nuclear-receptor–mediated regulation of drug– and bile-acid–transporter proteins in gut and liver

Abstract

Adverse drug events (ADEs) are a common cause of patient morbidity and mortality and are classically thought to result, in part, from variation in expression and activity of hepatic enzymes of drug metabolism. It is now known that alterations in the expression of genes that encode drug- and bile-acid–transporter proteins in both the gut and liver play a previously unrecognized role in determining patient drug response and eventual clinical outcome. Four nuclear receptor (NR) superfamily members, including pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (NR1I3), farnesoid X receptor (NR1H4), and vitamin D receptor (NR1I1), play pivotal roles in drug- and bile-acid– activated programs of gene expression to coordinately regulate drug- and bile-acid transport activity in the intestine and liver. This review focuses on the NR-mediated gene activation of drug and bile-acid transporters in these tissues as well as the possible underlying molecular mechanisms.

Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

“…In addition to FXR, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) which are two other nuclear receptors, have been shown to also play important roles in regulating transporters and enzymes of bile acid (Staudinger et al, 2013). However, AB23A had no effects on gene expression of Cyp3a11 which is a PXR target gene, and Cyp2b10 which is a CAR target gene in mice, suggesting that the hepatoprotection of AB23A is not through PXR and CAR activation.…”

Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

“…In addition to FXR, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) which are two other nuclear receptors, have been shown to also play important roles in regulating transporters and enzymes of bile acid (35). However, AB23A had no effects on gene expression of Cyp3a11 which is a PXR target gene, and Cyp2b10 which is a CAR target gene in mice, suggesting that the hepatoprotection of AB23A is not through PXR and CAR activation.…”

A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors

“…This protein responds to bile acid ligands by binding its cognate DNA-binding sites through a pair of Zn-fingers and activating transcription (Staudinger et al, 2013). Similar to HOXC10 and PITX2, deletion of the first Zn-finger of NR1H4 (amino acids 129-152) significantly diminished its ability to localize to damaged chromatin (Figures 5D and 5E).…”