Activated pregnenolone X-receptor is a target for ketoconazole and its analogs.

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Wang H, Huang H, Li H, Teotico DG, Sinz M, Baker SD, Staudinger J, Kalpana G, Redinbo MR, Mani S

Activated pregnenolone X-receptor is a target for ketoconazole and its analogs.

Clin Cancer Res. 2007 Apr 15;13(8):2488-95.

PubMed ID

17438109 [ View in PubMed

]

Abstract

PURPOSE: Variations in biotransformation and elimination of microtubule-binding drugs are a major cause of unpredictable side effects during cancer therapy. Because the orphan receptor, pregnenolone X-receptor (PXR), coordinately regulates the expression of paclitaxel metabolizing and transport enzymes, controlling this process could improve therapeutic outcome. EXPERIMENTAL DESIGN: In vitro RNA-, protein-, and transcription-based assays in multiple cell lines derived from hepatocytes and PXR wild-type and null mouse studies were employed to show the effects of ketoconazole and its analogues on ligand-activated PXR-mediated gene transcription and translation. RESULTS: The transcriptional activation of genes regulating biotransformation and transport by the liganded human nuclear xenobiotic receptor, PXR, was inhibited by the commonly used antifungal ketoconazole and related azole analogs. Mutations at the AF-2 surface of the human PXR ligand-binding domain indicate that ketoconazole may interact with specific residues outside the ligand-binding pocket. Furthermore, in contrast to that observed in PXR (+/+) mice, genetic loss of PXR results in increased (preserved) blood levels of paclitaxel. CONCLUSIONS: These studies show that some azole compounds repress the coordinated activation of genes involved in drug metabolism by blocking PXR activation. Because loss of PXR maintains blood levels of paclitaxel upon chronic dosing, ketoconazole analogues may also serve to preserve paclitaxel blood levels on chronic dosing of drugs. Our observations may facilitate new strategies to improve the clinical efficacy of drugs and to reduce therapeutic side effects.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Pregnenolone	Cytochrome P450 3A4	Protein	Humans	No	Substrate	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Paclitaxel	Approved Vet Approved	CYP3A4	1576	upregulated	Paclitaxel results in increased expression of CYP3A4 mRNA	7q22.1
Rifampicin	Approved	CYP2B6	1555	upregulated	Rifampin results in increased expression of CYP2B6 mRNA	19q13.2
Rifampicin	Approved	CYP3A4	1576	upregulated	Rifampin results in increased expression of CYP3A4 mRNA	7q22.1