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Enhanced transport of anticancer agents and leukotriene C 4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2)
Author(s) -
Kawabe Takeshi,
Chen Zhe-Sheng,
Wada Morimasa,
Uchiumi Takeshi,
Ono Mayumi,
Akiyama Shin-ichi,
Kuwano Michihiko
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)00979-5
Subject(s) - chinese hamster ovary cell , multidrug resistance associated protein 2 , chemistry , leukotriene c4 , cisplatin , p glycoprotein , microbiology and biotechnology , biochemistry , transporter , biology , atp binding cassette transporter , multiple drug resistance , receptor , leukotriene , immunology , genetics , chemotherapy , gene , antibiotics , asthma
We established stable human canalicular multispecific organic anion transporter ( cMOAT/MRP2 ) cDNA transfectants, CHO/cMOAT from non‐polarized Chinese hamster ovary (CHO)‐K1 and LLC/cMOAT from polarized pig kidney epithelial LLC‐PK1. Human cMOAT was mainly localized in the plasma membrane of CHO/cMOAT and in the apical membrane of LLC/cMOAT. The ATP‐dependent uptake of leukotriene C 4 (LTC 4 ) into CHO/cMOAT membrane vesicles was enhanced compared with empty vector transfectants. K m values in CHO/cMOAT membrane vesicles were 0.24 μM for LTC 4 and 175 μM for ATP. Drug sensitivity to vincristine and cisplatin in human cMOAT cDNA transfectants decreased, but not to etoposide. Cellular accumulation of vincristine and cisplatin in human cMOAT cDNA transfectants decreased, but not of etoposide. The uptake of LTC 4 into CHO/cMOAT membrane vesicles was inhibited by exogenous administration of vincristine or cisplatin, but not that of etoposide. Moreover, this inhibition was more enhanced in the presence of glutathione. These consequences indicate that drug resistance to vincristine or cisplatin appears to be modulated by human cMOAT through transport of the agents, possibly in direct or indirect association with glutathione.