Targeting the pregnane X receptor in liver injury.
BACKGROUND
The nuclear receptor pregnane X receptor (PXR) is a well-characterized hepatic xenobiotic sensor whose activation by chemically diverse compounds results in the induction of drug clearance pathways that rid the body of potentially toxic substances, thus conferring protection from foreign chemicals and endobiotics.


METHODS
PXR activities are implicated in drug-drug interactions and endocrine disruption. Recent evidence supports a hepatoprotective role for PXR in chronic liver injury, inhibiting liver inflammation through suppression of the NF-κB pathway. However, PXR-mediated induction of CYP3A enhances APAP-induced acute liver injury by generating toxic metabolites. While these observations implicate PXR as a therapeutic target for liver injury, they also caution against PXR activation by pharmaceutical drugs.


CONCLUSIONS
While evidence of PXR involvement in acute and chronic liver injuries identifies it as a possible therapeutic target, it raises additional concerns for all drug candidates. The in vitro and in vivo tests for human PXR activation should be incorporated into the FDA regulations for therapeutic drug approval to identify potential liver toxicities. In addition, PXR pharmacogenetic studies will facilitate the prediction of patient-specific drug reactivities and associated liver disorders.
The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Tao
T
Li
Ruth T
RT
Yu
Annette R
AR
Atkins
Michael
M
Downes
Robert H
RH
Tukey
Ronald M
RM
Evans
D000818:Animals; D006801:Humans; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid