TY - JOUR
T1 - Activated pregnenolone X-receptor is a target for ketoconazole and its analogs
AU - Wang, Hongwei
AU - Huang, Haiyan
AU - Li, Hao
AU - Teotico, Denise G.
AU - Sinz, Michael
AU - Baker, Sharyn D.
AU - Staudinger, Jeffrey
AU - Kalpana, Ganjam
AU - Redinbo, Matthew R.
AU - Mani, Sridhar
PY - 2007/4/15
Y1 - 2007/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34247871463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247871463&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-06-1592
DO - 10.1158/1078-0432.CCR-06-1592
M3 - Article
C2 - 17438109
AN - SCOPUS:34247871463
SN - 1078-0432
VL - 13
SP - 2488
EP - 2495
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -