Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor

Drug Metab Dispos. 2001 Nov;29(11):1467-72.


Identification and characterization of the pregnane X receptor (PXR) as a key regulator of cytochrome P450 3A (CYP3A) gene expression has led to an increased understanding of the molecular basis of many drug-drug interactions. Mice lacking PXR (PXR-KO) were used in the present study to delineate the role of PXR in regulating hepatomegaly and regulating the activity of CYP3A, organic anion transporting polypeptide-2 (Oatp2), and Cyp7a1 (cholesterol 7alpha-hydroxylase) gene products in vivo. Pregnenolone-16alpha-carbonitrile (PCN) produced hepatomegaly in the wild-type mice but not in the PXR-KO mice. PCN increased both the number of proliferating cell nuclear antigen immuno-positive nuclei and apparent cell size in the wild-type mice but not in the PXR-KO mice. To determine the role PXR plays in regulating CYP3A activity, 6beta-hydroxylation of testosterone and the duration of the loss of righting reflex following administration of the muscle-relaxant zoxazolamine were measured. PCN increased the level of testosterone 6beta-hydroxylation and decreased the duration of the loss of righting-reflex time following zoxazolamine administration in wild-type mice, but did not effect either of these parameters in PXR-KO mice. PCN increased the hepatic uptake of [(3)H]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-KO mice. Similarly, PCN decreased bile acid excretion in wild-type mice but not in the PXR-KO mice. Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Bile Acids and Salts / metabolism*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatomegaly / chemically induced
  • Hepatomegaly / metabolism
  • Homeostasis / physiology*
  • Mice
  • Mice, Knockout
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Organic Anion Transporters, Sodium-Independent / biosynthesis
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Oxidoreductases, N-Demethylating
  • Pregnane X Receptor
  • Pregnenolone Carbonitrile / toxicity
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Steroid / deficiency
  • Receptors, Steroid / genetics
  • Receptors, Steroid / physiology*
  • Xenobiotics / metabolism*


  • Bile Acids and Salts
  • Organic Anion Transporters, Sodium-Independent
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Slc22a7 protein, mouse
  • Xenobiotics
  • Pregnenolone Carbonitrile
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating