1. Cyclosporine-A induced cytotoxicity within HepG2 cells by inhibiting PXR mediated CYP3A4/CYP3A5/MRP2 pathway.
- Author
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Shang S, Li W, Zhou F, Zhao Y, Yu M, Tong L, Xin H, and Yu A
- Subjects
- Humans, Hep G2 Cells, Dose-Response Relationship, Drug, Cell Survival drug effects, Hepatocytes drug effects, Hepatocytes metabolism, Oxidative Stress drug effects, Immunosuppressive Agents toxicity, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Chemical and Drug Induced Liver Injury etiology, L-Lactate Dehydrogenase metabolism, Cyclosporine toxicity, Pregnane X Receptor metabolism, Pregnane X Receptor genetics, Cytochrome P-450 CYP3A metabolism, Cytochrome P-450 CYP3A genetics, Multidrug Resistance-Associated Protein 2, Multidrug Resistance-Associated Proteins metabolism, Multidrug Resistance-Associated Proteins genetics
- Abstract
Cyclosporine-A (CsA) is currently used to treat immune rejection after organ transplantation as a commonly used immunosuppressant. Liver injury is one of the most common adverse effects of CsA, whose precise mechanism has not been fully elucidated. Pregnane X receptor (PXR) plays a critical role in mediating drug-induced liver injury as a key regulator of drug and xenobiotic clearance. As a nuclear receptor, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters, including cytochrome P4503A (CPY3A) and multidrug resistance-associated protein 2 (MRP2). Our study established CsA-induced cytotoxic hepatocytes in an in vitro model, demonstrating that CsA dose-dependently increased the aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) level secreted in the HepG2 cell supernatant, as well as viability and oxidative stress of HepG2 cells. CsA also dose-dependently decreased the PXR, CYP3A4, CPY3A5, and MRP2 levels of HepG2 cells. Mechanistically, altering the expression of PXR, CYP3A4, CYP3A5, and MRP2 affected the impact of CsA on AST and LDH levels. Moreover, altering the expression of PXR also changed the level of CYP3A4, CPY3A5, and MRP2 of HepG2 cells treated by CsA. Our presented findings provide experimental evidence that CsA-induced liver injury is PXR tightly related. We suggest that PXR represents an attractive target for therapy of liver injury due to its central role in the regulation of the metabolizing enzymes CYP3A and MRP2-mediated bile acid transport and detoxification.
- Published
- 2024
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