Role of the Multidrug Resistance Protein 1 in protection from heavy metal oxyanions: investigations in vitro and in MRP1-deficient mice.
The Multidrug Resistance Protein 1 (MRP1) is a membrane pump that mediates the efflux of a wide variety of xenobiotics, including arsenical and antimonial compounds, as demonstrated by the study of MRP1-transfected cell lines. We have previously shown that mrp1(-/-) cells are hypersensitive to sodium arsenite, sodium arsenate, and antimony potassium tartrate. We now report that the retroviral vector-mediated overexpression of MRP1 and of the two subunits of gamma-GCS (heavy and light) resulted in higher intracellular glutathione levels and in a greater level of resistance to sodium arsenite and antimony potassium tartrate, compared to the overexpression of MRP1 and gamma-GCS heavy alone. These observations further demonstrate that glutathione is an important component of MRP1-mediated cellular resistance to arsenite and antimony. However, the constitutive expression of MRP1 did not protect mice from the lethality of sodium arsenite and antimony potassium tartrate nor reduced the tissue accumulation of arsenic in mice injected i.p. with sodium arsenite. It is conceivable that, in vivo, other pump(s) effectively vicariate for MRP1-mediated transport of heavy metal oxyanions.
Lorico
Aurelio
A
Department of Tumor Biology, Norwegian Radium Hospital, Montebello, 0310, Norway. aureliol@labmed.uio.no
Bertola
Antonella
A
Baum
Christopher
C
Fodstad
Oystein
O
Rappa
Germana
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000966:Antimony Potassium Tartrate / Q000633:toxicity*; D001151:Arsenic / Q000032:analysis; D018053:Arsenites / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005822:Genetic Vectors; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D019216:Metals, Heavy / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D012190:Retroviridae / Q000235:genetics; D017670:Sodium Compounds / Q000633:toxicity*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018053:Arsenites; D019216:Metals, Heavy; D017670:Sodium Compounds; C017947:sodium arsenite; D000966:Antimony Potassium Tartrate; D005978:Glutathione; D001151:Arsenic