Enhanced transport of anticancer agents and leukotriene C-4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2)

We established stable human canalicular multispecific organic anion transpo rter (cMOAT1MRP2) cDNA transfectants, CHO/cMOAT from non-polarized Chinese hamster ovary (CHO)-K1 and LLC/cMOAT from polarized pig kidney epithelial L LC-PK1. Human cMOAT was mainly localized in the plasma membrane of CHO/cMOA T and in the apical membrane of LLC/cMOAT. The ATP-dependent uptake of leuk otriene C-4 (LTC4) into CHO/cMOAT membrane vesicles was enhanced compared w ith empty vector transfectants, K-m values in CHO/cMOAT membrane vesicles w ere 0.24 mu M for LTC4 and 175 mu M for ATP. Drug sensitivity to vincristin e and cisplatin in human cMOAT cDNA transfectants decreased, but not to eto poside, Cellular accumulation of vincristine and cisplatin in human cMOA T cDNA transfectants decreased, but not of etoposide, The uptake of LTC4 into CHO/cMOAT membrane vesicles was inhibited by exogenous administration of v incristine or cisplatin, but not that of etoposide, Moreover, this inhibiti on was more enhanced in the presence of glutathione, These consequences ind icate that drug resistance to vincristine or cisplatin appears to be modula ted by human cMOAT through transport of the agents, possibly in direct or i ndirect association with glutathione. (C) 1999 Federation of European Bioch emical Societies.