Role of Pregnane X Receptor in Control of All-TransRetinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance

Abstract

Although all-trans-retinoic acid (ATRA) is an effective treatment for acute promyelocytic leukemia and several solid tumors, its use is limited by resistance due to increased metabolism. The most studied mechanism for ATRA resistance is the autoinduced metabolism regulated by the retinoic acid receptor-CYP26 pathway. However, treatment of cancer is usually not done with a single antineoplastic agent, but with a variety of combined chemotherapy regimens, including several anticancer drugs, and other concomitantly administered supportive drugs. Pregnane X receptor (PXR), an orphan nuclear receptor that functions as a ligand-activated transcription factor, serves as an important xenobiotic sensor regulating metabolism and elimination. Many prescription drugs are PXR ligands, which can activate PXR target genes, including phase I enzyme, phase II enzyme, and transporter genes. The present study was designed to examine the role of PXR in ATRA metabolism. Due to the marked species differences in response to PXR ligands, Pxr-null, wild-type, and PXR-humanized transgenic mouse models were used. In addition to pregnenolone 16alpha-carbonitrile, several clinically relevant PXR ligands (rifampicin and dexamethasone) all increased ATRA metabolism both in vitro and in vivo, which was PXR-dependent, and up-regulation of Cyp3a was the major contributor. Furthermore, induction of the Mdr1a, Mrp3, and Oatp2 genes was also observed. This study suggested that coadministration of PXR ligands can increase ATRA metabolism through activation of the PXR-CYP3A pathway, which might be a mechanism for some form of ATRA resistance. Other PXR target transporters might also be involved.