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Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole

Oncogene volume 26, pages 258–268 (2007)Cite this article

Abstract

Individual variation in drug metabolism is a major cause of unpredictable side effects during therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate expression of genes such as CYP (cytochrome)3A4 and MDR-1 (multi-drug resistance-1), that are involved in this process. We have found that xenobiotic-mediated induction of CYP3A4 and MDR-1 gene transcription was inhibited by ketoconazole, a commonly used antifungal drug. Ketoconazole mediated its effect by inhibiting the activation of NRs, human pregnenolone X receptor and constitutive androstene receptor, involved in regulation of CYP3A4 and MDR-1. The effect of ketoconazole was specific to the group of NRs that control xenobiotic metabolism. Ketoconazole disrupted the interaction of the xenobiotic receptor PXR with the co-activator steroid receptor co-activator-1. Ketoconazole treatment resulted in delayed metabolism of tribromoethanol anesthetic in mice, which was correlated to the inhibition of PXR activation and downmodulation of cyp3a11 and mdr-1 genes and proteins. These studies demonstrate for the first time that ketoconazole represses the coordinated activation of genes involved in drug metabolism, by blocking activation of a specific subset of NRs. Our results suggest that ketoconazole can be used as a pan-antagonist of NRs involved in xenobiotic metabolism in vivo, which may lead to novel strategies that improve drug effect and tolerance.

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Abbreviations

CAR:

constitutive androstene receptor

CYP:

cytochrome

DMSO:

dimethylsulfoxide

EcR:

ecdysone receptor

EGFR:

epidermal growth factor receptor

ELISA:

enzyme-linked immunosorbent assay

FBS:

fetal bovine serum

FXR:

farnesol X receptor

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

hPXR:

human pregnenolone X receptor

LXR:

liver activated receptor

MDR:

multidrug resistance

MDR-1:

multidrug resistance-1

PCN:

pregnenolone 16 α-carbonitrile

PPAR:

peroxisome proliferator-activated receptor

RAR:

retinoic acid receptor

RXR:

retinoid X receptor

SMRT:

silencing mediator of retinoid and thyroid hormone receptor

SRC-1:

steroid receptor co-activator-1

SXR:

steroid and xenobiotic receptor

TR:

thyroid receptor

UGT:

uridine glucuronosyl transferase

VDR:

vitamin D receptor

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Acknowledgements

We thank Drs Ronald Evans, Hilda Ye and I David Goldman for helpful and insightful discussions. Dr Kenny Ye from the Department of Epidemiology and Biostatistics of Albert Einstein College of Medicine provided statistical support and advised on statistical methods used in this manuscript. This study was supported by a grant from the Damon Runyon Cancer Research Foundation (CI: 15-02 to SM) and a grant from ACS (#CCG-104933) to GVK.

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Authors and Affiliations

  1. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA

    H Huang, H Wang, G V Kalpana & S Mani

  2. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    H Huang, H Wang & S Mani

  3. Bristol Myers Squibb Co., Wallingford, CT, USA

    M Sinz & M Zoeckler

  4. Department of Toxicology, University of Kansas, Lawrence, KS, USA

    J Staudinger

  5. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    M R Redinbo & D G Teotico

  6. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA

    J Locker

  7. Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

    G V Kalpana & S Mani

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  1. H Huang
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Correspondence to S Mani.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Huang, H., Wang, H., Sinz, M. et al. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 26, 258–268 (2007). https://doi.org/10.1038/sj.onc.1209788

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