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

H. Huang, H. Wang, M. Sinz, M. Zoeckler, J. Staudinger, M. R. Redinbo, D. G. Teotico, J. Locker, Ganjam V. Kalpana, Sridhar Mani

Research output: Contribution to journalArticle

150 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)258-268
Number of pages11
JournalOncogene
Volume26
Issue number2
DOIs
StatePublished - Jan 11 2007

Fingerprint

Ketoconazole
Cytoplasmic and Nuclear Receptors
Xenobiotics
Pharmaceutical Preparations
Multiple Drug Resistance
Cytochrome P-450 CYP3A
Androstenes
Orphan Nuclear Receptors
Drug Tolerance
Steroid Receptors
Cytochromes
Transcriptional Activation
Anesthetics
Gene Expression
Genes

Keywords

  • Drug metabolism
  • Orphan nuclear receptors
  • Transcriptional regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Huang, H., Wang, H., Sinz, M., Zoeckler, M., Staudinger, J., Redinbo, M. R., ... Mani, S. (2007). Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene, 26(2), 258-268. https://doi.org/10.1038/sj.onc.1209788

Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. / Huang, H.; Wang, H.; Sinz, M.; Zoeckler, M.; Staudinger, J.; Redinbo, M. R.; Teotico, D. G.; Locker, J.; Kalpana, Ganjam V.; Mani, Sridhar.

In: Oncogene, Vol. 26, No. 2, 11.01.2007, p. 258-268.

Research output: Contribution to journalArticle

Huang, H, Wang, H, Sinz, M, Zoeckler, M, Staudinger, J, Redinbo, MR, Teotico, DG, Locker, J, Kalpana, GV & Mani, S 2007, 'Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole', Oncogene, vol. 26, no. 2, pp. 258-268. https://doi.org/10.1038/sj.onc.1209788
Huang H, Wang H, Sinz M, Zoeckler M, Staudinger J, Redinbo MR et al. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene. 2007 Jan 11;26(2):258-268. https://doi.org/10.1038/sj.onc.1209788
Huang, H. ; Wang, H. ; Sinz, M. ; Zoeckler, M. ; Staudinger, J. ; Redinbo, M. R. ; Teotico, D. G. ; Locker, J. ; Kalpana, Ganjam V. ; Mani, Sridhar. / Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. In: Oncogene. 2007 ; Vol. 26, No. 2. pp. 258-268.
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