Regulation of expression and activity of multidrug resistance proteins MRP2 and MDR1 by estrogenic compounds in Caco-2 cells. Role in prevention of xenobiotic-induced cytotoxicity.

ARIAS, A; RIGALLI, JP; VILLANUEVA , SS; RUIZ, ML; LUQUITA, MG; PERDOMO , VG; VORE M; CATANIA, VA; MOTTINO, AD

TOXICOLOGY

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2014 vol. 320 p. 46 - 55

0300-483X

tABC transporters including MRP2, MDR1 and BCRP play a major role in tissue defense. Epidemiologicaland experimental studies suggest a cytoprotective role of estrogens in intestine, though the mechanismremains poorly understood. We evaluated whether pharmacologic concentrations of ethynylestradiol(EE, 0.05 pM to 5 nM), or concentrations of genistein (GNT) associated with soy ingestion (0.1?10 M),affect the expression and activity of multidrug resistance proteins MRP2, MDR1 and BCRP using Caco-2cells, an in vitro model of intestinal epithelium. We found that incubation with 5 pM EE and 1 M GNTfor 48 h increased expression and activity of both MRP2 and MDR1. Estrogens did not affect expres-sion of BCRP protein at any concentration studied. Irrespective of the estrogen tested, up-regulation ofMDR1 and MRP2 protein was accompanied by increased levels of MDR1 mRNA, whereas MRP2 mRNAremained unchanged. Cytotoxicity assays demonstrated association of MRP2 and MDR1 up-regulationwith increased resistance to cell death induced by 1-chloro-2,4-dinitrobenzene, an MRP2 substrate pre-cursor, and by paraquat, an MDR1 substrate. Experiments using an estrogen receptor (ER) antagonistimplicate ER participation in MRP2 and MDR1 regulation. GNT but not EE increased the expression of ER,the most abundant form in human intestine and in Caco-2 cells, which could lead in turn to increased sen-sitivity to estrogens. We conclude that specific concentrations of estrogens can confer resistance againstcytotoxicity in Caco-2 cells, due in part to positive modulation of ABC transporters involved in extrusionof their toxic substrates. Although extrapolation of these results to the in vivo situation must be cautiouslydone, the data could explain tentatively the cytoprotective role of estrogens against chemical injury inintestine