TY - JOUR
T1 - PXR antagonists and implication in drug metabolism
AU - Mani, Sridhar
AU - Dou, Wei
AU - Redinbo, Matthew R.
N1 - Funding Information:
Funding for work presented in this review came from the Albert Einstein Cancer Center (Albert Einstein College of Medicine, Bronx, New York, USA) as well as grants from the National Institutes of Health (CA 127231) and the Damon Runyon Foundation Clinical Investigator Award (CI15-02, and National Natural Science Foundation of China (81150040, 81273572)).
PY - 2013/2
Y1 - 2013/2
N2 - Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno-and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno-(e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application.
AB - Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno-and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno-(e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application.
KW - Adverse drug interactions
KW - Antagonist
KW - Drug metabolism
KW - Pharmcophore
KW - Pregnane x receptor
UR - http://www.scopus.com/inward/record.url?scp=84872735872&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872735872&partnerID=8YFLogxK
U2 - 10.3109/03602532.2012.746363
DO - 10.3109/03602532.2012.746363
M3 - Review article
C2 - 23330542
AN - SCOPUS:84872735872
SN - 0360-2532
VL - 45
SP - 60
EP - 72
JO - Drug Metabolism Reviews
JF - Drug Metabolism Reviews
IS - 1
ER -