TY - JOUR
T1 - Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2)
AU - Kawabe, Takeshi
AU - Chen, Zhe Sheng
AU - Wada, Morimasa
AU - Uchiumi, Takeshi
AU - Ono, Mayumi
AU - Akiyama, Shin Ichi
AU - Kuwano, Michihiko
N1 - Funding Information:
This study was supported by grants from Second-Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health and Welfare, Japan, and also CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation (JST).
PY - 1999/8/6
Y1 - 1999/8/6
N2 - 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 C4 (LTC4) 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 LTC4 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 LTC4 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. Copyright (C) 1999 Federation of European Biochemical Societies.
AB - 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 C4 (LTC4) 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 LTC4 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 LTC4 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. Copyright (C) 1999 Federation of European Biochemical Societies.
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U2 - 10.1016/S0014-5793(99)00979-5
DO - 10.1016/S0014-5793(99)00979-5
M3 - Article
C2 - 10456333
AN - SCOPUS:0032781499
SN - 0014-5793
VL - 456
SP - 327
EP - 331
JO - FEBS Letters
JF - FEBS Letters
IS - 2
ER -