The Pregnane X Receptor Regulates Gene Expression in a Ligand- and Promoter- Selective Fashion

Abstract

Recent studies have revealed that pregnane X receptor (PXR) can function as a master regulator to control the expression of phase I and phase II drug-metabolizing enzymes, as well as members of the drug transporter family, including multiple drug resistance (MDR) 1, which has a major role in multidrug resistance. Previously, we have demonstrated that steroid/xenobiotics metabolism by tumor tissue through the PXR-cytochrome P-450 3A (CYP3A) pathway might play an important role in endometrial cancer. In this study, we examined which endocrine-disrupting chemicals (EDCs) and anticancer agents might be ligands for PXR and whether these chemicals enhanced PXR-mediated transcription through two different PXR-responsive elements (PXREs), CYP3A4 and MDR1, in endometrial cancer cell lines. Some steroids/EDCs strongly activated PXR-mediated transcription through the CYP3A4-responsive element compared with the MDR1-responsive element, whereas these steroids/EDCs also enhanced the CYP3A4 expression compared with the MDR1 expression. In contrast, the anticancer agents, cisplatin and paclitaxel, strongly activated PXR-mediated transcription through the MDR1-responsive element compared with the CYP3A4-responsive element, whereas these drugs also enhanced the MDR1 expression compared with the CYP3A4 expression. We also analyzed how these ligands regulated PXR-mediated transcription through two different PXREs. In the presence of PXR ligands, there was no difference in the DNA binding affinity of the PXR/retinoid X receptor heterodimer to each PXRE, but there were different interactions of the coactivator to each PXR/PXRE complex. These data suggested that PXR ligands enhanced PXR-mediated transcription in a ligand- and promoter-dependent fashion, which in turn differentially regulated the expression of individual PXR targets, especially CYP3A4 and MDR1.

Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways

“…1, 3B, and 4). We hypothesize that this discrepancy can be explained considering the report of Masuyama et al (2005), who demonstrated a ligand-and promoter-specific fashion of PXR-mediated transcription of CYP3A4 and MDR1 genes.…”

CYP450 polymorphisms predict clinic outcomes to vinorelbine-based chemotherapy in patients with non-small-cell lung cancer

“…We only focused on drug metabolism, but the full spectrum of drug disposition, including a growing list of transporters that influence drug absorption, distribution, and excretion should also be taken into account. Expression of CYP450 is also regulated by other genes such as PXR and CAR [11,14,15]. The outcome may also be influenced by the polymorphisms of these genes.…”

Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

“…Similar to CYP3A4, PXR-dependent activation of P-gp by rifampin has been demonstrated [32] . PXR can also be activated by several chemotherapeutic agents, including paclitaxel [23] and cisplatin [54] . Synold et al showed that paclitaxel-activated hPXR induced hepatic expression of CYP3A4 and CYP2C8, as well as MDR1 expression in intestinal tumor cells resulting in enhanced metabolism of paclitaxel by CYP3A4 and CYP2C8, and excretion from the intestine via P-gp.…”