1. ¹Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA
2. ²Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
3. ³Bristol Myers Squibb Co., Wallingford, CT, USA
4. ⁴Department of Toxicology, University of Kansas, Lawrence, KS, USA
5. ⁵Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
6. ⁶Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
7. ⁷Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

Correspondence: Dr S Mani, Department of Oncology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 302D-1, Bronx, NY 10461, USA. E-mail: smani@montefiore.org

Received 4 May 2006; Revised 30 May 2006; Accepted 30 May 2006; Published online 3 July 2006.

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.