Multidrug-resistance mdr1a/1b double knockout mice are more sensitive than wild type mice to acute arsenic toxicity, with higher arsenic accumulation in tissues

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 mdrla/l b( -/- ) mice, which lack mdrla-type P-glycoproteins. to examine whether these mice are sensitive to arsenic toxicity and have higher arsenic accumulation in their tissues. The mdrl a/l b(- / - ) and wild- type FVB mice were given arsenic as sodium arsenite (12-19 mg/kg, sc) and toxicity was examined 24 h later. The mdrla/lb( - / -) mice were more sensitive than wild-type mice to arsenite-induced lethality, with LD50 of 14.5 and 17 mg/kg, respectively. Histologically, arsenite produced more frequent and more severe lesions in the liver and kidney of the mdrla/lb(-/-) mice than in wild-type mice. Serum alanine amino transferase activity and blood urea nitrogen levels, indicative of hepatic and renal damage respectively, were increased 4 to 6-fold in the mdrla/lb(-/-) mice as compared with 1-2-fold increases in wild-type mice. The mdrla/lb(-/-) mice accumulated more arsenic in the liver (15.3 vs. 5.2 mug/g), kidney (7.23 vs. 3.22 mug/g), small intestine (3.98 vs 1.57 mug/g) and brain (0.45 vs. 0.17 mug/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 mdrla/lb( - / -) 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. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

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