TY - JOUR
T1 - Characterization of in vitro Mrp2 transporter model based on intestinal organoids
AU - Zhang, Lei
AU - Liang, Chenmeizi
AU - Xu, Peipei
AU - Liu, Mingyao
AU - Xu, Feng
AU - Wang, Xin
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/11
Y1 - 2019/11
N2 - Multidrug resistance associated protein 2 (MRP2) is an important efflux transporter involved in clinical drug disposition and drug-drug interactions. The study of MRP2-mediated drug transport has become an integral part of drug discovery and development. In particular, screening of specific MRP2 inhibitors will help overcome the multidrug resistance in cancer. In this report, a new method for rapid and sensitive detection of Mrp2 function was established via using mouse small intestinal organoids. Firstly, small intestinal crypts isolated from mouse intestine were induced by Noggin, R-spondin1 and EGF to develop three-dimensional (3D) organoids. Secondly, the 3D organoids were characterized by the physical and physiological structure of Mrp2-mediated drug transport. Finally, Mrp2 fluorescent substrate 5(6)-carboxyl- 2′, 7′-dichlorofluorescein (CDF) and its inhibitor MK-571 and probenecid were used to demonstrate Mrp2-mediated CDF transport in 3D organoids. The results showed that the small intestinal organoids have a physiological structure for Mrp2-mediated compound transport. Moreover, MK-571 and probenecid, inhibitors of MRP2, significantly decreased the accumulation of CDF in 3D organoids. In summary, a novel intestinal organoid model has been successfully established for the rapid and effective study of Mrp2-mediated drug transport.
AB - Multidrug resistance associated protein 2 (MRP2) is an important efflux transporter involved in clinical drug disposition and drug-drug interactions. The study of MRP2-mediated drug transport has become an integral part of drug discovery and development. In particular, screening of specific MRP2 inhibitors will help overcome the multidrug resistance in cancer. In this report, a new method for rapid and sensitive detection of Mrp2 function was established via using mouse small intestinal organoids. Firstly, small intestinal crypts isolated from mouse intestine were induced by Noggin, R-spondin1 and EGF to develop three-dimensional (3D) organoids. Secondly, the 3D organoids were characterized by the physical and physiological structure of Mrp2-mediated drug transport. Finally, Mrp2 fluorescent substrate 5(6)-carboxyl- 2′, 7′-dichlorofluorescein (CDF) and its inhibitor MK-571 and probenecid were used to demonstrate Mrp2-mediated CDF transport in 3D organoids. The results showed that the small intestinal organoids have a physiological structure for Mrp2-mediated compound transport. Moreover, MK-571 and probenecid, inhibitors of MRP2, significantly decreased the accumulation of CDF in 3D organoids. In summary, a novel intestinal organoid model has been successfully established for the rapid and effective study of Mrp2-mediated drug transport.
KW - Drug transport
KW - Intestinal organoids
KW - Mouse
KW - Multidrug resistance-associated protein 2 (Mrp2)
KW - Transporter model
UR - https://www.scopus.com/pages/publications/85071388429
U2 - 10.1016/j.yrtph.2019.104449
DO - 10.1016/j.yrtph.2019.104449
M3 - 文章
C2 - 31449916
AN - SCOPUS:85071388429
SN - 0273-2300
VL - 108
JO - Regulatory Toxicology and Pharmacology
JF - Regulatory Toxicology and Pharmacology
M1 - 104449
ER -
