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Issue 25, 2017, Issue in Progress

Identification of drug transporters involved in the uptake and efflux of rhein in hepatocytes

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Abstract

Aim: Rhein is a herbal medicine with various bioactivities and is derived from an anthraquinone compound. In this study, we aimed to identify drug transporters involved in the uptake and efflux of rhein in hepatocytes. Methods: Rhein uptake and efflux were investigated in rat liver slices, primary rat hepatocytes, human transporter-transfected cells, membrane vesicles, and rats. Rhein was quantified using liquid chromatography-tandem mass spectrometry. Results: Rhein uptake was fitted to a Michaelis–Menten model with a Km = 229.4 ± 58.5 μM and Vmax = 428.7 ± 49.2 pmol mg−1 protein in liver slices and a Km = 129.6 ± 22.3 μM and Vmax = 9.1 ± 0.6 nmol mg−1 protein in primary rat hepatocytes. Rhein uptake by primary rat hepatocytes was inhibited by organic anion-transporting polypeptide (OATP) inhibitors (rifampicin and fluvastatin) and an organic anion transporter (OAT) inhibitor (probenecid). Rhein was taken up by HEK293 cells expressing OATP1B3, OATP2B1, and OAT2 and pumped out of MDCKII cells expressing breast cancer resistance protein (BCRP), but not from those expressing P-glycoprotein (P-gp) or from membrane vesicles expressing multidrug resistance-associated proteins (MRPs) 2 and 3. In rats, hepatic exposure to rhein was reduced by rifampicin and probenecid (AUC0–2 h decreased 0.61- and 0.12-fold, respectively), but increased by pantoprazole (AUC0–2 h increased 0.64-fold), a BCRP inhibitor. Conclusion: These results show that OATP1B3, OATP2B1, and OAT2 contribute to hepatic rhein uptake, while BCRP contributes to its hepatic efflux. The results provide new insights into the mechanisms of rhein uptake and efflux in hepatocytes.

Graphical abstract: Identification of drug transporters involved in the uptake and efflux of rhein in hepatocytes

Article information


Submitted
14 Dec 2016
Accepted
27 Feb 2017
First published
07 Mar 2017

This article is Open Access

RSC Adv., 2017,7, 15236-15245
Article type
Paper

Identification of drug transporters involved in the uptake and efflux of rhein in hepatocytes

Y. Dai, B. Ma, M. Zheng, R. Shi, Y. Li, T. Wang and Y. Ma, RSC Adv., 2017, 7, 15236 DOI: 10.1039/C6RA28205A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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