The Function of Multidrug Resistance-associated Protein 3 in the Transport of Bile Acids under Normal Physiological and Lithocholic Acid-induced Cholestasis Conditions
| Autor: | Lingzhi Gong, Zhongqiu Liu, Wenyu Wang, Ming Hu, Sijing Zeng |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Lithocholic acid medicine.drug_class Clinical Biochemistry Bile Acids and Salts chemistry.chemical_compound Mice Cholestasis Internal medicine medicine Animals Enterohepatic circulation Pharmacology Mice Knockout Kidney Bile acid Chemistry Physiological condition Gallbladder Wild type medicine.disease Mice Inbred C57BL Endocrinology medicine.anatomical_structure Liver Lithocholic Acid Multidrug Resistance-Associated Proteins |
| Zdroj: | Current drug metabolism. 22(5) |
| ISSN: | 1875-5453 |
| Popis: | Background: The role of multidrug resistance-associated protein 3 (Mrp3) in the transport of bile acid (BA) in drug-induced cholestasis has not been well studied. Objective: In this study, wild type and Mrp3 knockout (Mrp3-/-) mice under normal physiological and lithocholic acid (LCA)-induced cholestatic conditions were employed to investigate the role of Mrp3 in BA transport. Method: The levels of BA in serum, liver, gallbladder, intestine, kidney, feces and urine were quantified in both wild type and Mrp3-/- mice via ultra-high performance liquid chromatography triple quadrupole mass spectrometry (UHPLC-MS/MS). Quantitative real-time PCR (RT-PCR) analysis was used to measure the expression of genes related to the transport and synthesis of BA. Results: The results showed that the liver did not suffer more serious damage as a result of cholestasis when Mrp3 was depleted. The level of some individual bile acids changed apparently in the compartments of enterohepatic circulation (EHC) between the two control and model groups, respectively, but the level of serum total bile acid was only slightly reduced for Mrp3-/- groups. In addition, the level of BA-related efflux transporters and synthases increased significantly when Mrp3 was knocked out under normal physiological conditions, but a negligible alteration appeared under cholestatic conditions. Conclusion: Our results indicated that Mrp3 could be responsible for the transport of some specific bile acids, and part of the Mrp3 role could be compensated for by other transporters. Moreover, Mrp3 deficiency has a direct effect on the expression of BA-related synthases and efflux transporters under normal physiological conditions, but this effect could be less prominent under cholestatic conditions. This study could provide much valuable insight into the physiological function of Mrp3 in the transport of bile acids. |
| Databáze: | OpenAIRE |
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