Online citations, reference lists, and bibliographies.
← Back to Search

The Orphan Nuclear Receptor SXR Coordinately Regulates Drug Metabolism And Efflux

T. Synold, I. Dussault, B. M. Forman
Published 2001 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy Visualize in Litmaps
Share
Reduce the time it takes to create your bibliography by a factor of 10 by using the world’s favourite reference manager
Time to take this seriously.
Get Citationsy
Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein–mediated drug clearance. In contrast, docetaxel (Taxotere), a closely related antineoplastic agent, did not activate SXR and displayed superior pharmacokinetic properties. Docetaxel's silent properties reflect its inability to displace transcriptional corepressors from SXR. We also found that ET-743, a potent antineoplastic agent, suppressed MDR1 transcription by acting as an inhibitor of SXR. These findings demonstrate how the molecular activities of SXR can be manipulated to control drug clearance.
This paper references
10.1097/00008571-199412000-00001
Biochemistry and molecular biology of the human CYP2C subfamily.
J. Goldstein (1994)
10.1016/0092-8674(95)90075-6
Unique response pathways are established by allosteric interactions among nuclear hormone receptors
B. M. Forman (1995)
10.1136/gut.36.2.259
Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues.
R. McKinnon (1995)
10.1016/0092-8674(95)90193-0
15-Deoxy-Δ 12,14-Prostaglandin J 2 is a ligand for the adipocyte determination factor PPARγ
B. M. Forman (1995)
10.1006/ABBI.1995.1291
Isolation and characterization of a new cDNA clone belonging to the cytochrome P450 2C gene subfamily in hamsters.
T. Sakuma (1995)
Metabolism of docetaxel by human cytochromes P450: interactions with paclitaxel and other antineoplastic drugs.
I. Royer (1996)
10.1210/MEND.11.6.0004
The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT.
T. A. Jackson (1997)
10.1093/AJHP/54.SUPPL_2.S2
Antitumor activity of docetaxel.
J. Eckardt (1997)
10.1073/PNAS.94.5.2031
Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine.
A. Sparreboom (1997)
10.1002/j.1875-9114.1997.tb03811.x
Pharmacology of the Taxanes
R. Dorr (1997)
10.1002/j.1875-9114.1997.tb03812.x
Pharmacokinetics of the Taxanes
C. Kearns (1997)
10.1210/MEND.11.6.0009
Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen.
C. L. Smith (1997)
10.1073/PNAS.94.9.4312
Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ
B. Forman (1997)
Biotransformation of taxoids by human cytochromes P450: structure-activity relationship.
B. Monsarrat (1997)
10.1023/A:1008224322396
In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients.
E. Izbicka (1998)
10.1097/00001813-199801000-00001
Preclinical pharmacokinetics of paclitaxel and docetaxel.
A. Sparreboom (1998)
10.1016/S0092-8674(00)80900-9
An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway
S. Kliewer (1998)
10.1101/GAD.12.20.3195
SXR, a novel steroid and xenobiotic-sensing nuclear receptor.
B. Blumberg (1998)
10.1038/26996
Androstane metabolites bind to and deactivate the nuclear receptor CAR-β
B. Forman (1998)
10.1073/PNAS.95.6.2920
Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes.
R. M. Lavinsky (1998)
10.1006/ABBI.1998.0730
Induction of cytochrome P4503A by taxol in primary cultures of human hepatocytes.
V. Kostrubsky (1998)
10.1080/004982598238859
Human cytochrome P450s: selectivity and measurement in vivo.
D. Smith (1998)
10.1146/ANNUREV.PHARMTOX.39.1.361
Biochemical, cellular, and pharmacological aspects of the multidrug transporter.
S. Ambudkar (1999)
The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue.
Helmut Dotzlaw (1999)
10.1016/S1097-2765(00)80348-2
Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.
H. Wang (1999)
10.2165/00003088-199936020-00002
Clinical Pharmacokinetics of Docetaxel
S. Clarke (1999)
10.1073/PNAS.96.7.3496
Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743.
E. J. Martinez (1999)
10.1124/MOL.56.5.851
Molecular mechanisms of cytochrome P-450 induction by xenobiotics: An expanded role for nuclear hormone receptors.
U. Savas (1999)
10.1073/PNAS.130155097
St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.
L. B. Moore (2000)
10.1073/PNAS.97.12.6775
Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation.
S. Jin (2000)
10.1074/JBC.M001215200
Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid Ligands*
L. B. Moore (2000)
10.1182/BLOOD.V95.9.2897.009K14_2897_2904
P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway.
M. Pallis (2000)
10.1006/BBRC.2000.3219
Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes.
J. Pascussi (2000)
10.1073/PNAS.97.12.6780
Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743.
M. Minuzzo (2000)
Effects of the multidrug transporter P-glycoprotein on cellular responses to ionizing radiation.
A. Ruth (2000)
10.1101/GAD.14.2.121
The coregulator exchange in transcriptional functions of nuclear receptors.
C. Glass (2000)
10.1210/ME.14.1.27
The Pregnane X Receptor: A Promiscuous Xenobiotic Receptor That Has Diverged during Evolution
S. Jones (2000)
10.1016/S0140-6736(00)02074-2
The taxanes: an update
J. Crown (2000)
10.1677/JOE.0.166R011
St John's wort, a herbal antidepressant, activates the steroid X receptor.
J. M. Wentworth (2000)
10.1038/35019116
Humanized xenobiotic response in mice expressing nuclear receptor SXR
W. Xie (2000)
10.1016/S0092-8674(00)00064-7
Combinatorial Roles of the Nuclear Receptor Corepressor in Transcription and Development
K. Jepsen (2000)
10.1073/pnas.051551698
The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity
Jeff L. Staudinger (2001)
10.1016/S0303-7207(00)00395-6
The expression of pregnane X receptor and its target gene, cytochrome P450 3A1, in perinatal mouse
H. Masuyama (2001)



This paper is referenced by
10.3390/biom11081142
Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment
Aikaterini Skandalaki (2021)
10.3390/nu13051709
Effect of Vitamin K-Mediated PXR Activation on Drug-Metabolizing Gene Expression in Human Intestinal Carcinoma LS180 Cell Line
H. Sultana (2021)
10.1080/03602532.2021.1874406
Molecular modeling approaches to address drug-metabolizing enzymes (DMEs) mediated chemoresistance: a review
Baddipadige Raju (2021)
10.1016/j.drup.2020.100742
Taxanes in cancer treatment: Activity, chemoresistance and its overcoming.
L. Mosca (2021)
10.1007/s00280-021-04352-9
Megestrol acetate is a specific inducer of CYP3A4 mediated by human pregnane X receptor
Yakun Chen (2021)
10.1016/j.ejphar.2020.173023
Z-guggulsterone regulates MDR1 expression mainly through the pregnane X receptor-dependent manner in human brain microvessel endothelial cells.
H. Xu (2020)
10.1007/s00018-020-03505-y
Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning
Andrew D. Huber (2020)
10.5772/intechopen.92712
Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential Effects on Bioavailability and Disposition of Tyrosine Kinase Inhibitors
M. Iqbal (2020)
10.3390/ph13090218
Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells
Yun Soo Jeong (2020)
10.1080/17425255.2020.1779701
PXR-mediated idiosyncratic drug-induced liver injury: mechanistic insights and targeting approaches
Jingheng Wang (2020)
10.3892/ijo.2020.5100
Role of taurine, its haloamines and its lncRNA TUG1 in both inflammation and cancer progression. On the road to therapeutics? (Review)
Stella Baliou (2020)
10.1039/d0fo00315h
Citrus auraptene induces drug efflux transporter P-glycoprotein expression in human intestinal cells.
T. Nabekura (2020)
10.1016/j.drudis.2020.07.023
Cancer stem cells and nanomedicine: new opportunities to combat multidrug resistance?
A. Dalpiaz (2020)
10.1016/j.bbrep.2020.100727
Microtubule-targeting anticancer drug eribulin induces drug efflux transporter P-glycoprotein
T. Nabekura (2020)
10.1016/j.biopha.2020.110434
Low dose HSP90 inhibition with AUY922 blunts rapid evolution of metastatic and drug resistant phenotypes induced by TGF-β and paclitaxel in A549 cells.
Nickolas A. Bacon (2020)
10.1124/jpet.119.264762
Phosphorylation Modulates the Coregulatory Protein Exchange of the Nuclear Receptor Pregnane X Receptor
Wenqi Cui (2020)
10.3390/ijms21186885
Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies
Ingrid Lilienthal (2020)
10.1021/acsmedchemlett.0c00076
Characterization of an Alginate Encapsulated LS180 Spheroid Model for Anti-colorectal Cancer Compound Screening.
T. Smit (2020)
10.3390/cells9102295
Associations between Pregnane X Receptor and Breast Cancer Growth and Progression
B. Creamer (2020)
Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P 450 3 A 4 in human hepatocytes
Jian Yang (2019)
10.1016/j.ejps.2019.105039
BRD4 PROTAC as a novel therapeutic approach for the treatment of vemurafenib resistant melanoma: Preformulation studies, formulation development and in vitro evaluation.
Drishti Rathod (2019)
10.1158/0008-5472.CAN-18-3024
Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy.
Changlong Liu (2019)
10.1039/c9nr04495g
Fucoidan-coated coral-like Pt nanoparticles for computed tomography-guided highly enhanced synergistic anticancer effect against drug-resistant breast cancer cells.
Seounghun Kang (2019)
10.1080/10799893.2019.1694541
Functional role of miR-148a in oropharyngeal cancer: influence on pregnane X receptor and P-glycoprotein expression
T. Reuter (2019)
10.21037/jtd.2019.08.01
TMEM213 as a novel prognostic and predictive biomarker for patients with lung adenocarcinoma after curative resection: a study based on bioinformatics analysis.
Jia-Yun Zou (2019)
10.1007/978-981-13-7647-4_6
Roles of Hepatic Drug Transporters in Drug Disposition and Liver Toxicity.
Guoyu Pan (2019)
10.1080/15384101.2019.1693120
TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR
Ella Bhagyaraj (2019)
10.1111/jcpt.13084
Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population
Weihua Ren (2019)
10.1016/j.ejmech.2019.06.066
Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance.
Chao-Yun Cai (2019)
10.3390/md17100554
Marine Ligands of the Pregnane X Receptor (PXR): An Overview
Alejandro Carazo (2019)
10.1007/s00280-019-03905-3
Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes
Maarten van Eijk (2019)
10.3390/ijms20112844
Multiple Modes of Vitamin K Actions in Aging-Related Musculoskeletal Disorders
K. Azuma (2019)
See more
Semantic Scholar Logo Some data provided by SemanticScholar