Regulation of tissue-specific carboxylesterase expression by pregnane x receptor and constitutive androstane receptor.
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.
Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Drive, 5038a Malott Hall, Lawrence, KS 66045, USA.
Chenshu
C
Xu
Xinkun
X
Wang
Jeff L
JL
Staudinger
D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D011987:Receptors, Steroid / Q000378:metabolism / Q000502:physiology*; D051603:Recoverin / Q000235:genetics / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology*
D000090702:Constitutive Androstane Receptor; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; C496732:Rcvrn protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D051603:Recoverin; D011285:Pregnenolone Carbonitrile; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C500145:Ces2c protein, mouse