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
16α-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