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Research ArticleMetabolism, Transport, and Pharmacogenomics

An Insulin-Like Growth Factor 1 Receptor Inhibitor Induces CYP3A4 Expression through a Pregnane X Receptor-Independent, Noncanonical Constitutive Androstane Receptor-Related Mechanism

Linhao Li, Michael W. Sinz, Kurt Zimmermann and Hongbing Wang
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 688-697; DOI: https://doi.org/10.1124/jpet.111.188854
Linhao Li
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Michael W. Sinz
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Kurt Zimmermann
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Hongbing Wang
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Abstract

Inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling represents an attractive therapeutic strategy for cancer treatment. A first-generation IGF-1R inhibitor (R)-4-(3-(3-chlorophenyl)-3-hydroxypropyl)-3-(4-methyl-6-morpholino-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-536924), however, was associated with potent CYP3A4 induction mediated by pregnane X receptor (PXR; NR1I2) transactivation. Structural activity-based modification led to the synthesis of 4-(1-(2-(4-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-1H-benzo[d]imidazol-6-yl)piperidin-4-yl) piperazine-1-carboxylate (BMS-665351) with no PXR activity while maintaining its ability to inhibit IGF-1R. However, BMS-665351 significantly induces CYP3A4 expression in human primary hepatocytes (HPHs). Here, we report a novel nonclassical constitutive androstane receptor (CAR; NR1I3)-related pathway of BMS-665351-mediated CYP3A4 induction. BMS-665351 treatment resulted in the significant induction of CYP3A4 in HPHs and HepG2 cells, but failed to activate either PXR or CAR in cell-based reporter assays. Moreover, BMS-665351 at concentrations that induce CYP3A4 expression was unable to translocate human CAR from the cytoplasm to the nucleus of HPHs, which represents the initial step of CAR activation. Nevertheless, quantitative polymerase chain reaction analysis demonstrated that BMS-665351 significantly enhanced the expression of CYP3A4 in CAR- but not PXR-transfected HepG2 and Huh7 cells. It is noteworthy that BMS-665351 selectively induced the expression of CAR but not PXR in all tested hepatic cell systems. Synergistic induction of CYP3A4 was observed in HPHs cotreated with BMS-665351 and prototypical activators of CAR but not PXR. In summary, our results indicate that BMS-665351-mediated induction of CYP3A4 is CAR-dependent, but BMS-665351 itself is not a typical activator of either CAR or PXR, rather it functions as a selective inducer of CAR expression and increases CYP3A4 through a noncanonical CAR-related mechanism.

Footnotes

  • This research was supported by a research agreement with Bristol-Meyer Squibb; and funding from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK061652] (to H.W.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.188854.

  • ABBREVIATIONS:

    IGF-1R
    insulin-like growth factor-1 receptor
    Act.D
    actinomycin D
    CAR
    constitutive androstane receptor
    hCAR
    human CAR
    Ad/EYFP-hCAR
    adenovirus-expressing enhanced yellow florescent protein tagged hCAR
    CHX
    cycloheximide
    DDI
    drug-drug interaction
    DMSO
    dimethyl sulfoxide
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    GR
    glucocorticoid receptor
    HPH
    human primary hepatocyte
    CITCO
    6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime
    PB
    phenobarbital
    PXR
    pregnane X receptor
    hPXR
    human PXR
    PXRE
    proximal everted repeat-6 element
    RIF
    rifampicin
    PK11195
    1-(2-chlorophenyl-N-methylpropyl)-3-isoquinoline-carboxamide
    RT-PCR
    reverse transcription-polymerase chain reaction
    VDR
    vitamin D receptor
    XREM
    xenobiotic-responsive enhancer module
    BMS-665351
    4-(1-(2-(4-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-1H-benzo[d]imidazol-6-yl)piperidin-4-yl)piperazine-1-carboxylate
    BMS-536924
    (R)-4-(3-(3-chlorophenyl)-3-hydroxypropyl)-3-(4-methyl-6-morpholino-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one.

  • Received October 7, 2011.
  • Accepted December 6, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Nonclassical CAR-Dependent Induction of CYP3A4 Expression

Linhao Li, Michael W. Sinz, Kurt Zimmermann and Hongbing Wang
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 688-697; DOI: https://doi.org/10.1124/jpet.111.188854

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Nonclassical CAR-Dependent Induction of CYP3A4 Expression

Linhao Li, Michael W. Sinz, Kurt Zimmermann and Hongbing Wang
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 688-697; DOI: https://doi.org/10.1124/jpet.111.188854
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