Abstract
Differential regulation of drug-metabolizing enzymes (DMEs) is a common cause of adverse drug effects in cancer therapy. Due to the extremely important role of cytochrome P450 3A4 (CYP3A4) in drug metabolism and the dominant regulation of human pregnane X receptor (hPXR) on CYP3A4, finding inhibitors for hPXR could provide a unique tool to control drug efficacies in cancer therapy. Camptothecin (CPT) was demonstrated as a novel and potent inhibitor (IC50 = 0.58 μM) of an hPXR-mediated transcriptional regulation on CYP3A4 in this study. In contrast, one of its analogs, irinotecan (CPT-11), was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 but had effects on neither the competition of ligand binding nor the formation of the hPXR and retinoid X receptor α heterodimer, nor the interaction between the regulatory complex and DNA-responsive elements. CPT treatment resulted in delayed metabolism of nifedipine in human hepatocytes treated with rifampicin, suggesting a potential prevention of drug-drug interactions between CYP3A4 inducers and CYP3A4-metabolized drugs. Because CPT is the leading compound of topoisomerase I inhibitors, which comprise a quickly developing class of anticancer agents, the findings indicate the potential of a new class of compounds to modify hPXR activity as agonists/inhibitors and are important in the development of CPT analogs.
Footnotes
This work was supported by the Fiscal Year 2009 Penny Severn postdoctoral fellowship from Offices of Women's Health, Illinois Department of Public Health; the U.S. Department of Defense postdoctoral prostate cancer training award [Grant PC081012]; and the National Institutes of Health National Cancer Institute [Grants R15-CA133776, R01-CA13345].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.168294.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- CPT
- camptothecin
- DME
- drug-metabolizing enzyme
- hPXR
- human pregnane X receptor
- DDI
- drug-drug interaction
- SRC-1
- steroid receptor cofactor-1
- 1,25-(OH)2VD3
- 1α 25-dihydroxyvitamin D3
- CITCO
- 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
- PCN
- pregnenolone-16α-carbonitrile
- SRC186
- 186 amino acid residues of the human SRC-1 protein
- SR12813
- [[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetraethyl ester
- PCR
- polymerase chain reaction
- EMSA
- electrophoretic mobility shift assay
- HPLC
- high-performance liquid chromatography
- hVDR
- human vitamin D receptor
- hCAR3
- human constitutive androstane receptor 3
- mPXR
- mouse pregnane X receptor
- RXRα
- retinoid X receptor α
- RT
- reverse transcription
- CMV
- cytomegalovirus
- LBD
- ligand binding domain
- DSMO
- dimethyl sulfoxide
- FRET
- fluorescence resonance energy transfer
- TR
- time resolved
- MDR-1
- multidrug resistance gene-1
- MRP-1
- multiple drug resistance protein-1
- hPXRE
- human pregnane X receptor-responsive element
- ER
- everted repeat
- A-792611
- methyl 1-(5-(2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate
- ET-743
- (1′R,6R,6aR,7R,13S,14S,16R)-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-19-oxo-3′,4′,6,7,12,13,14,16-octahydrospiro[6,16-(epithiopropano oxymethano)-7,13-imino-6aH-1,3-dioxolo[7,8]isoquino [3,2-b][3]benzazocine-20,1′(2′H)-isoquinolin]-5-yl acetate
- IR
- inverted repeat.
- Received March 18, 2010.
- Accepted May 25, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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