Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2)

FEBS Letters

Akiyama, Shin-ichi²  Chen, Zhe-Sheng²  Kuwano, Michihiko¹  Uchiumi, Takeshi¹  Wada, Morimasa¹  Kawabe, Takeshi¹  Ono, Mayumi¹ 

[1] Department of Biochemistry, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuraga-oka 890-8520, Japan

关键词: cMOAT;    MRP family;    ABC transporter;    Multidrug resistance;    Anticancer agent;   

DOI  :  10.1016/S0014-5793(99)00979-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown