Activation of xenobiotic receptors: driving into the nucleus.
BACKGROUND
Xenobiotic receptors (XRs) play pivotal roles in regulating the expression of genes that determine the clearance and detoxification of xenobiotics, such as drugs and environmental chemicals. Recently, it has become increasingly evident that most XRs shuttle between the cytoplasm and nucleus, and activation of such receptors is directly associated with xenobiotic-induced nuclear import.


METHODS
The scope of this review covers research literature that discusses nuclear translocation and activation of XRs, as well as unpublished data generated from this laboratory. Specific emphasis is given to the constitutive androstane receptor (CAR), the pregnane X receptor and the aryl hydrocarbon receptor.


RESULTS
A number of molecular chaperons presumably associated with cellular localization of XRs have been identified. Primary hepatocyte cultures have been established as a unique model retaining inactive CAR in the cytoplasm. Moreover, several splicing variants of human CAR exhibit altered cellular localization and chemical activation.


CONCLUSIONS
Nuclear accumulation is an essential step in the activation of XRs. Although great strides have been made, much remains to be understood concerning the mechanisms underlying intracellular localization and trafficking of XRs, which involve both direct ligand-binding and indirect pathways.
Li
Haishan
H
University of Maryland School of Pharmacy, Department of Pharmaceutical Sciences, 20 Penn Street, Baltimore, MD 21201, USA.
Wang
Hongbing
H
D021581:Active Transport, Cell Nucleus; D000818:Animals; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*
D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics