title: Multidrug-resistance mdr1a/1b double knockout mice are more sensitive than wild type mice to acute arsenic toxicity, with higher arsenic accumulation in tissues.
abstract: Arsenic is an environmental toxicant. Active extrusion via the ArsAB pump is a mechanism for arsenic detoxication in bacteria. However, how arsenic is effluxed from mammalian cells is not completely known. Our recent work shows that acquired arsenic resistance is associated with overexpression of P-glycoprotein and can be reversed by PSC833, an inhibitor for P-glycoprotein. This study utilized the mdr1a/1b(-/-) mice, which lack mdr1-type P-glycoproteins, to examine whether these mice are sensitive to arsenic toxicity and have higher arsenic accumulation in their tissues. The mdr1a/1b(-/-) and wild-type FVB mice were given arsenic as sodium arsenite (12-19 mg/kg, sc) and toxicity was examined 24 h later. The mdr1a/1b(-/-) mice were more sensitive than wild-type mice to arsenite-induced lethality, with LD(50) of 14.5 and 17 mg/kg, respectively. Histologically, arsenite produced more frequent and more severe lesions in the liver and kidney of the mdr1a/1b(-/-) mice than in wild-type mice. Serum alanine aminotransferase activity and blood urea nitrogen levels, indicative of hepatic and renal damage respectively, were increased 4 to 6-fold in the mdr1a/1b(-/-) mice as compared with 1-2-fold increases in wild-type mice. The mdr1a/1b(-/-) mice accumulated more arsenic in the liver (15.3 vs. 5.2 microg/g), kidney (7.23 vs. 3.22 microg/g), small intestine (3.98 vs. 1.57 microg/g) and brain (0.45 vs. 0.17 microg/g), as compared with wild-type mice 24 h after sodium arsenite (14 mg/kg, s.c.) administration. In summary, this study demonstrated that the mdr1a/1b(-/-) mice were more sensitive to acute arsenic toxicity and accumulated more arsenic than wild-type mice, suggesting that P-glycoproteins are involved, at least in part, in arsenic efflux in mammalians.
authors.affiliation: Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, Mail Drop F0-09, NCI at NIEHS, 111, Alexander Drive, Research Triangle Park, NC 27709, USA. liu6@niehs.nih.gov
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Powell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001151:Arsenic / Q000493:pharmacokinetics* / Q000633:toxicity*; D018053:Arsenites / Q000378:metabolism; D001806:Blood Urea Nitrogen; D019450:Genes, MDR / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D014018:Tissue Distribution
chemical_list: D018053:Arsenites; D000410:Alanine Transaminase; D001151:Arsenic