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


METHODS
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.
Wang
Hongwei
H
Albert Einstein Cancer Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Huang
Haiyan
H
Li
Hao
H
Teotico
Denise G
DG
Sinz
Michael
M
Baker
Sharyn D
SD
Staudinger
Jeffrey
J
Kalpana
Ganjam
G
Redinbo
Matthew R
MR
Mani
Sridhar
S
D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007654:Ketoconazole / Q000031:analogs & derivatives / Q000494:pharmacology*; D008113:Liver Neoplasms; D008156:Luciferases / Q000235:genetics; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000187:drug effects / Q000502:physiology*
D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D008156:Luciferases; D007654:Ketoconazole