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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Antifungal Agents / pharmacology*
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Blotting, Western
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Constitutive Androstane Receptor
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / genetics*
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Cytochrome P-450 Enzyme System / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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Ethanol / analogs & derivatives
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Ethanol / metabolism
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Female
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Gene Expression Regulation / drug effects*
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Hepatocytes / metabolism
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Histone Acetyltransferases / antagonists & inhibitors
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Humans
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Ketoconazole / pharmacology*
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Liver X Receptors
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nuclear Receptor Coactivator 1
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Orphan Nuclear Receptors
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Pregnane X Receptor
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
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Receptors, Steroid / antagonists & inhibitors
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / antagonists & inhibitors
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Tumor Cells, Cultured
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antifungal Agents
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Constitutive Androstane Receptor
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DNA-Binding Proteins
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Liver X Receptors
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Orphan Nuclear Receptors
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Pregnane X Receptor
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Transcription Factors
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tribromoethanol
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Ethanol
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Cytochrome P-450 Enzyme System
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Histone Acetyltransferases
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NCOA1 protein, human
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Ncoa1 protein, mouse
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Nuclear Receptor Coactivator 1
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Ketoconazole