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Multidrug resistance associated protein 1 protects against bilirubin‐induced cytotoxicity
Author(s) -
Calligaris Sebastián,
Cekic Dean,
Roca-Burgos Leslye,
Gerin Fabio,
Mazzone Graciela,
Ostrow J. Donald,
Tiribelli Claudio
Publication year - 2006
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/j.febslet.2006.01.056
Subject(s) - cytotoxicity , lactate dehydrogenase , bilirubin , efflux , toxicity , multidrug resistance associated protein 2 , intracellular , chemistry , biochemistry , microbiology and biotechnology , in vitro , atp binding cassette transporter , pharmacology , biology , transporter , enzyme , endocrinology , gene , organic chemistry
We have shown that multidrug resistance associated protein 1 (MRP1) mediates ATP‐dependent extrusion of bilirubin, possibly limiting its potentially toxic accumulation in cells. To determine directly if Mrp1 protects cells against unconjugated bilirubin (UCB) toxicity, mouse embryo fibroblasts (MEF) were isolated from Mrp1 knockout (−/−) mice and their wild type (WT) (+/+) littermates. Compared to WT cells, cultured MEF (−/−) cells exposed to 40–140 nM unbound [H 3 ]‐bilirubin accumulated twice as much [H 3 ]‐bilirubin ( P < 0.01). This was associated with greater, dose‐related cytotoxicity, assessed by the methylthiazoletetrazolium test, lactate dehydrogenase release and cellular ATP content. The data confirm that Mrp1 limits intracellular accumulation of UCB and thus decreases its cytotoxicity.