Nuclear receptor-mediated regulation of carboxylesterase expression and activity.
BACKGROUND
Emerging evidence demonstrates that several nuclear receptor (NR) family members regulate drug-inducible expression and activity of several important carboxylesterase (CES) enzymes in mammalian liver and intestine. Numerous clinically prescribed anticancer prodrugs, carbamate and pyrethroid insecticides, environmental toxicants and procarcinogens are substrates for CES enzymes. Moreover, a key strategy used in rational drug design frequently utilizes an ester linkage methodology to selectively target a prodrug, or to improve the water solubility of a novel compound.


METHODS
This review summarizes the current state of knowledge regarding NR-mediated regulation of CES enzymes in mammals and highlights their importance in drug metabolism, drug-drug interactions and toxicology.


RESULTS
New knowledge regarding the transcriptional regulation of CES enzymes by NR proteins pregnane x receptor (NR1I2) and constitutive androstane receptor (NR1I3) has recently come to light through the use of knockout and transgenic mouse models. Novel insights regarding the species-specific cross-regulation of glucocorticoid receptor (NR3C1) and PPAR-alpha (NR1C1) signaling and CES gene expression are discussed.


CONCLUSIONS
Elucidation of the role of NR-mediated regulation of CES enzymes in liver and intestine will have a significant impact on rational drug design and the development of novel prodrugs, especially for patients on combination therapy.
Staudinger
Jeff L
JL
Department of Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA. stauding@ku.edu
Xu
Chenshu
C
Cui
Yue J
YJ
Klaassen
Curtis D
CD
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*
D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D004364:Pharmaceutical Preparations; D018160:Receptors, Cytoplasmic and Nuclear; D002265:Carboxylic Ester Hydrolases