Activation of xenobiotic receptors: driving into the nucleus

Abstract

Importance of the field-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.Areas covered in this review-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scope of this review covers research literature that discusses nuclear translocation and activation of XRs, as well as unpublished data generated from this laboratory.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.What the readers will gain-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.Take home message-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.

Downregulation of CYP3A and P-Glycoprotein in the Secondary Inflammatory Response of Mice With Dextran Sulfate Sodium–Induced Colitis and Its Contribution to Cyclosporine A Blood Concentrations

“…Importantly, the timing of changes in CYP3A and P-gp expression was consistent with that of up-regulation of inflammatory markers in the liver and upper small intestine. The transcriptional activation of CYP3A and P-gp is mediated by nuclear receptors, and PXR, CAR, and RXRa have a key role in this mechanism (40,41). In the livers of DSS-treated mice on day 7, significant suppression of PXR was observed, but there was no suppression of CAR or RXRa.…”

An update on the constitutive androstane receptor (CAR)

“…Displacement of labeled clotrimazole from the CAR LBD by test compounds [ 159 ] has the disadvantage that it cannot distinguish between agonists and inverse agonists. Due to the high basal activity and complex activation mechanisms of CAR as well as rather tedious protocols and/or technical issues, these assays are only low-throughput and/or prone to false positives [ 17 ].…”

Targeting xenobiotic receptors PXR and CAR in human diseases

“…These xenobiotic receptors are known to bind various structurally diverse chemicals [7,8]. Because they regulate an overlapping set of target genes, it is difficult to dictate their specificity in gene regulation and associated biological functions [9]. PXR is expressed in normal tissues such as liver, intestine, colon, kidney, brain, breast, prostate, peripheral mononuclear blood cells, heart, bone marrow, spinal cord, stomach, ovary, placenta and immune cells; as well as in many human cancers, including breast, prostate, colon, osteosarcoma, ovarian and endometrial cancers, with elevated expression in some cancers [10,11].…”