Regulation of tissue-specific carboxylesterase expression by pregnane x receptor and constitutive androstane receptor

Drug Metab Dispos. 2009 Jul;37(7):1539-47. doi: 10.1124/dmd.109.026989. Epub 2009 Apr 9.

Abstract

The liver- and intestine-enriched carboxylesterase 2 (CES2) enzyme catalyzes the hydrolysis of several clinically important anticancer agents administered as prodrugs. For example, irinotecan, a carbamate prodrug used in the treatment of colorectal cancer, is biotransformed in vivo by CES2 in intestine and liver, thereby producing a potent topoisomerase I inhibitor. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of ligand-activated transcription factors, mediate gene activation in response to xenobiotic stress. Together, these receptors comprise a protective response in mammals that coordinately regulate hepatic transport, metabolism, and elimination of numerous xenobiotic compounds. In the present study, microarray analysis was used to identify PXR target genes in duodenum in mice. Here, we show that a gene encoding a member of the CES2 subtype of liver- and intestine-enriched CES enzymes, called Ces6, is induced after treatment with pregnenolone 16alpha-carbonitrile in a PXR-dependent manner in duodenum and liver in mice. Treatment of mice with the CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene also induced expression of Ces6 in duodenum and liver in a CAR-dependent manner, whereas treatment with phenobarbital produced induction of Ces6 exclusively in liver. These data identify a key role for PXR and CAR in regulating the drug-inducible expression and activity of an important CES enzyme in vivo. Future studies should focus on determining whether these signaling pathways governing drug-inducible CES expression in intestine and liver are conserved in humans.

MeSH terms

  • Animals
  • Carboxylesterase
  • Carboxylic Ester Hydrolases / genetics
  • Carboxylic Ester Hydrolases / metabolism*
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Duodenum / metabolism
  • Gene Expression / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology*
  • Liver / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Pregnane X Receptor
  • Pregnenolone Carbonitrile / pharmacology
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Steroid / metabolism
  • Receptors, Steroid / physiology*
  • Recoverin / genetics
  • Recoverin / metabolism
  • Xenobiotics / pharmacology*

Substances

  • Membrane Proteins
  • Pregnane X Receptor
  • RNA, Messenger
  • Rcvrn protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Xenobiotics
  • Recoverin
  • Pregnenolone Carbonitrile
  • constitutive androstane receptor
  • Cyp3a11 protein, mouse
  • Cytochrome P-450 CYP3A
  • Carboxylic Ester Hydrolases
  • Carboxylesterase
  • Ces2c protein, mouse