RT Journal Article
SR Electronic
T1 Activation of PXR-Cytochrome P450s axis: A Possible Reason for the Enhanced Accelerated Blood Clearance Phenomenon of PEGylated Liposomes in vivo
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.086769
DO 10.1124/dmd.119.086769
A1 Feng L. Wang
A1 Hui H. Wang
A1 Yi Fan Wu
A1 Lei Wang
A1 Ling Zhang
A1 Xi Ye
A1 Dai Y. Peng
A1 Wei D. Chen
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/05/22/dmd.119.086769.abstract
AB Recently, we reported that repeated injection of PEGylated liposomes (PEG-L) at certain intervals to the same rat lead to the disappearance of their long-circulating properties, referred to as "accelerated blood clearance (ABC)" phenomenon. Evidence from our recent studies suggest cytochrome P450s (CYPs) partly contribute to the induction of the ABC phenomenon, which had previously been ignored. However, little is known about the details of the mechanism for the induction of CYPs. This study was undertaken to investigate the roles of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the ABC phenomenon, which are the major upstream transcriptional regulators of the CYP genes including CYP3A1, CYP2C6 and CYP1A2. The results demonstrated that the expression of rat PXR and CAR were significantly increased in such phenomenon, accompanied by elevated CYP3A1, CYP2C6 and CYP1A2 levels. Further findings revealed that PXR but not CAR protein was substantially upregulated in the hepatocyte nucleus, together with marked nuclear co-localization of PXR-retinoid X receptor alpha (RXRα) transcriptionally active heterodimer, indicating that nuclear translocation of PXR was induced in the ABC phenomenon, whereas nuclear translocation of CAR was not observed. Notably, pretreatment with the specific PXR inducer-dexamethasone significantly induced accelerated systemic clearance of the subsequent injection of PEG-L, associating with increased nuclear co-localization of PXR-RXRα. These results revealed that the induction of CYPs in the ABC phenomenon may be largely attributable to the activation of PXR induced by sequential injections of PEG-L, thus confirming the crucial involvement of PXR-CYPs axis in promoting ABC phenomenon.SIGNIFICANCE STATEMENT The results of this study revealed that the induction of CYPs in the ABC phenomenon may be largely attributable to the activation of PXR induced by sequential injections of PEG-L, thus confirming the crucial involvement of PXR-CYPs axis in promoting ABC phenomenon. The data may help to extend our insights into 1) the role of CYPs, which are regulated by the liver-enriched nuclear receptor PXR, in the ABC phenomenon, and 2) the therapeutic potential of targeting the PXR-CYP axis for reducing the magnitude of the ABC phenomenon in clinical practice.