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Drug Metab Dispos. 2019 Aug;47(8):785-793. doi: 10.1124/dmd.119.086769. Epub 2019 May 22.

Activation of Pregnane X Receptor-Cytochrome P450s Axis: A Possible Reason for the Enhanced Accelerated Blood Clearance Phenomenon of PEGylated Liposomes In Vivo.

Author information

1
Institute of Drug Metabolism (F.W., H.W., Y.W., L.W., L.Z., D.P., W.C.) and Institute of Pharmaceutics (W.C.), School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei, Anhui, China; Department of Pharmacy, The Second People's Hospital of Hefei, Hefei, Anhui, China (F.W., X.Y.); Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China (L.W., L.Z., D.P., W.C.); and Synergetic Innovation Center of Anhui Authentic Chinese Medicine Quality Improvement, Hefei, China (D.P., W.C.).
2
Institute of Drug Metabolism (F.W., H.W., Y.W., L.W., L.Z., D.P., W.C.) and Institute of Pharmaceutics (W.C.), School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei, Anhui, China; Department of Pharmacy, The Second People's Hospital of Hefei, Hefei, Anhui, China (F.W., X.Y.); Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China (L.W., L.Z., D.P., W.C.); and Synergetic Innovation Center of Anhui Authentic Chinese Medicine Quality Improvement, Hefei, China (D.P., W.C.) pengdy@ahtcm.edu.cn.
3
Institute of Drug Metabolism (F.W., H.W., Y.W., L.W., L.Z., D.P., W.C.) and Institute of Pharmaceutics (W.C.), School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei, Anhui, China; Department of Pharmacy, The Second People's Hospital of Hefei, Hefei, Anhui, China (F.W., X.Y.); Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China (L.W., L.Z., D.P., W.C.); and Synergetic Innovation Center of Anhui Authentic Chinese Medicine Quality Improvement, Hefei, China (D.P., W.C.) wdchen@ahtcm.edu.cn.

Abstract

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-circulation properties, referred to as the "accelerated blood clearance (ABC) phenomenon". Evidence from our recent studies suggested that cytochrome P450s (P450s) contribute to induction of the ABC phenomenon, a possibility that had been previously ignored. However, few details are known about the mechanism for induction of P450s. The present study was undertaken to investigate the roles in the ABC phenomenon of pregnane X receptor (PXR) and constitutive androstane receptor (CAR), the major upstream transcriptional regulators of the P450 genes, including CYP3A1, CYP2C6, and CYP1A2. The results demonstrated that expression of rat PXR and CAR was significantly increased in the ABC phenomenon and was 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 colocalization of the 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 colocalization of PXR-RXRα These results revealed that the induction of P450s in the ABC phenomenon may be attributable largely to the activation of PXR induced by sequential injections of PEG-L, thus confirming the crucial involvement of the PXR-P450s axis in promoting the ABC phenomenon. SIGNIFICANCE STATEMENT: The results of this study revealed that the induction of P450s 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 the PXR-P450s axis in promoting the ABC phenomenon. The data may help to extend our insights into 1) the role of P450s, which are regulated by the liver-enriched nuclear receptor PXR, in the ABC phenomenon, and 2) the therapeutic potential of targeting the PXR-P450 axis for reducing the magnitude of the ABC phenomenon in clinical practice.

PMID:
31118196
DOI:
10.1124/dmd.119.086769

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