PMID- 33333074
OWN - NLM
STAT- MEDLINE
DCOM- 20210422
LR  - 20220905
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 184
DP  - 2021 Feb
TI  - Characterization of human pregnane X receptor activators identified from a 
      screening of the Tox21 compound library.
PG  - 114368
LID - S0006-2952(20)30604-3 [pii]
LID - 10.1016/j.bcp.2020.114368 [doi]
AB  - The pregnane X receptor (PXR; NR1I2) is an important nuclear receptor whose main 
      function is to regulate enzymes within drug metabolism. The main drug 
      metabolizing enzyme regulated by PXR, cytochrome P450 (CYP) 3A4, accounts for the 
      metabolism of nearly 50% of all marketed drugs. Recently, PXR has also been 
      identified as playing a role in energy homeostasis, immune response, and cancer. 
      Due to its interaction with these important roles, alongside its drug-drug 
      interaction function, it is imperative to identify compounds which can modulate 
      PXR. In this study, we screened the Tox21 10,000 compound collection to identify 
      hPXR agonists using a stable hPXR-Luc HepG2 cell line. A pharmacological study in 
      the presence of a PXR antagonist was performed to confirm the activity of the 
      chosen potential hPXR agonists in the same cells. Finally, metabolically 
      competent cell lines - HepaRG and HepaRG-PXR-Knockout (KO) - were used to further 
      confirm the potential PXR activators. We identified a group of structural 
      clusters and singleton compounds which included potentially novel hPXR agonists. 
      Of the 21 selected compounds, 11 potential PXR activators significantly induced 
      CYP3A4 mRNA expression in HepaRG cells. All of these compounds lost their 
      induction when treating HepaRG-PXR-KO cells, confirming their PXR activation. 
      Etomidoline presented as a potentially selective agonist of PXR. In conclusion, 
      the current study has identified 11 compounds as potentially novel or not 
      well-characterized PXR activators. These compounds should further be studied for 
      their potential effects on drug metabolism and drug-drug interactions due to the 
      immense implications of being a PXR agonist.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Lynch, Caitlin
AU  - Lynch C
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health, Bethesda, MD, United States.
FAU - Sakamuru, Srilatha
AU  - Sakamuru S
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health, Bethesda, MD, United States.
FAU - Huang, Ruili
AU  - Huang R
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health, Bethesda, MD, United States.
FAU - Niebler, Jake
AU  - Niebler J
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health, Bethesda, MD, United States.
FAU - Ferguson, Stephen S
AU  - Ferguson SS
AD  - Division of the National Toxicology Program, National Institute of Environmental 
      Health Sciences, NIH, Durham, NC, United States.
FAU - Xia, Menghang
AU  - Xia M
AD  - National Center for Advancing Translational Sciences, National Institutes of 
      Health, Bethesda, MD, United States. Electronic address: mxia@mail.nih.gov.
LA  - eng
GR  - Z99 TR999999/ImNIH/Intramural NIH HHS/United States
GR  - ZIA TR000038/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20201214
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Cytochrome P-450 CYP3A Inducers)
RN  - 0 (NR1I2 protein, human)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Small Molecule Libraries)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
SB  - IM
MH  - Cytochrome P-450 CYP3A/genetics
MH  - Cytochrome P-450 CYP3A Inducers/pharmacology
MH  - Gene Knockout Techniques
MH  - HEK293 Cells
MH  - Hep G2 Cells
MH  - High-Throughput Screening Assays/*methods
MH  - Humans
MH  - Pregnane X Receptor/*agonists/antagonists & inhibitors/genetics/*metabolism
MH  - Reproducibility of Results
MH  - Small Molecule Libraries
PMC - PMC9440615
MID - NIHMS1831540
OTO - NOTNLM
OT  - Agonist
OT  - Pregnane X receptor
OT  - Quantitative high-throughput screening
OT  - Tox21
EDAT- 2020/12/18 06:00
MHDA- 2021/04/23 06:00
PMCR- 2022/09/03
CRDT- 2020/12/17 20:10
PHST- 2020/10/05 00:00 [received]
PHST- 2020/12/09 00:00 [revised]
PHST- 2020/12/10 00:00 [accepted]
PHST- 2020/12/18 06:00 [pubmed]
PHST- 2021/04/23 06:00 [medline]
PHST- 2020/12/17 20:10 [entrez]
PHST- 2022/09/03 00:00 [pmc-release]
AID - S0006-2952(20)30604-3 [pii]
AID - 10.1016/j.bcp.2020.114368 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2021 Feb;184:114368. doi: 10.1016/j.bcp.2020.114368. Epub 2020 
      Dec 14.