Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism

Arch Biochem Biophys. 2005 Jan 15;433(2):397-412. doi: 10.1016/j.abb.2004.09.019.

Abstract

Drugs and bile acids are taken up into hepatocytes by specialized transport proteins localized at the basolateral membrane, e.g., organic anion transporting polypeptides . Following intracellular metabolism by cytochrome P450 (CYP) enzymes, drug metabolites are excreted into bile or urine via ATP-dependent multidrug resistance proteins (MDR1 and MRPs). Bile acids are excreted mainly via the bile salt export pump (BSEP, ABCB11). The genes coding for drug and bile acid transporters and CYP enzymes are regulated by a complex network of transcriptional cascades, notably by the ligand-activated nuclear receptors FXR, PXR, and CAR and by the ligand-independent nuclear receptor HNF-4alpha. The bile acid synthesizing enzymes CYP7A1, CYP8B1, and CYP27A1 are subject to negative feedback regulation by bile acids, which is partly mediated through the transcriptional repressor SHP. The role of transcriptional cofactors, such as SRC-1 and PGC-1, in mediating the gene-specific effects of individual nuclear receptors is becoming increasingly evident.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism*
  • Cholestanetriol 26-Monooxygenase
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA-Binding Proteins / metabolism
  • Feedback, Physiological
  • Forecasting
  • Heat-Shock Proteins / metabolism
  • Hepatocyte Nuclear Factor 4
  • Histone Acetyltransferases
  • Homeostasis*
  • Humans
  • Ligands
  • Models, Biological
  • Multidrug Resistance-Associated Proteins / metabolism
  • Nuclear Receptor Coactivator 1
  • Pharmaceutical Preparations / metabolism*
  • Phosphoproteins / metabolism
  • Pregnane X Receptor
  • Receptors, Calcitriol / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Steroid / metabolism
  • Receptors, Virus / metabolism
  • Steroid 12-alpha-Hydroxylase / metabolism
  • Steroid Hydroxylases / metabolism
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • Bile Acids and Salts
  • CLMP protein, human
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • DNA-Binding Proteins
  • HNF4A protein, human
  • Heat-Shock Proteins
  • Hepatocyte Nuclear Factor 4
  • Ligands
  • Multidrug Resistance-Associated Proteins
  • Pharmaceutical Preparations
  • Phosphoproteins
  • Pregnane X Receptor
  • Receptors, Calcitriol
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Glucocorticoid
  • Receptors, Steroid
  • Receptors, Virus
  • Trans-Activators
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • farnesoid X-activated receptor
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Cholesterol 7-alpha-Hydroxylase
  • CYP27A1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • Steroid 12-alpha-Hydroxylase
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1