The MRP1-mediated effluxes of arsenic and antimony do not require arsenic-glutathione and antimony-glutathione complex formation.
Arsenic trioxide is an effective treatment for acute promyelocytic leukemia, but resistance to metalloid salts is found in humans. Using atomic absorption spectroscopy, we have measured the rate of uptake of arsenic trioxide and of antimony tartrate in GLC4 and GLC4/ADR cells overexpressing MRP1 and the rate of their MRP1-mediated effluxes as a function of the intracellular GSH concentration. In sensitive cells, after 1 h, a pseudosteady state is reached where intra- and extracellular concentrations of metalloid are the same. This precludes the formation, at short term, of complexes between arsenic or antimony with GSH. In resistant cells reduced intracellular accumulation of arsenic (or antimony), reflecting an increased rate of arsenic (or antimony) efflux from the cells, is observed. No efflux of the metalloid is observed in GSH depleted cells. The two metalloids and GSH are pumped out by MRP1 with the same efficiency. Moreover for the three compounds 50% of the efflux is inhibited by 2 microM MK571. This led us to suggest that As- and Sb-containing species could be cotransported with GSH.
Salerno
Milena
M
Laboratoire de Physicochimie Biornoléculaire et Cellulaire (UMR CNRS 7033), Université Paris Nord, Bobigny, France.
Petroutsa
Maria
M
Garnier-Suillerot
Arlette
A
D000965:Antimony / Q000493:pharmacokinetics*; D000966:Antimony Potassium Tartrate / Q000493:pharmacokinetics; D001151:Arsenic / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000493:pharmacokinetics; D001693:Biological Transport, Active; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000493:pharmacokinetics; D013054:Spectrophotometry, Atomic; D014407:Tumor Cells, Cultured
D000965:Antimony; D000966:Antimony Potassium Tartrate; D001151:Arsenic; D000077237:Arsenic Trioxide; D001152:Arsenicals; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010087:Oxides; C421109:multidrug resistance-associated protein 1