Multidrug-resistance mdr1a/1b double knockout mice are more sensitive than wild type mice to acute arsenic toxicity, with higher arsenic accumulation in tissues
Multidrug-resistance mdr1a/1b double knockout mice are more sensitive than wild type mice to acute arsenic toxicity, with higher arsenic accumulation in tissues
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DOI：
10.1016/s0300-483x(01)00532-7
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发表时间：
2002-01-15
期刊：
影响因子：
4.5
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Liu, J;Liu, YP;Klaassen, CD
砷是一种环境毒物。通过 ArsAB 泵主动挤出是细菌中砷解毒的机制。然而，砷如何从哺乳动物细胞中流出尚不完全清楚。我们最近的工作表明，获得性砷抗性与 P-糖蛋白的过度表达有关，并且可以被 P-糖蛋白抑制剂 PSC833 逆转。本研究使用了 mdrla/lb( -/- ) 小鼠，其缺乏 mdrla 型 P-糖蛋白。检查这些小鼠是否对砷毒性敏感并在其组织中积累较高的砷积累。 mdrl a/lb(- / - ) 和野生型 FVB 小鼠以亚砷酸钠（12-19 mg/kg，皮下）给予砷，并在 24 小时后检查毒性。 mdrla/lb(-/-)小鼠比野生型小鼠对亚砷酸盐致死更敏感，LD50分别为14.5和17 mg/kg。组织学上，亚砷酸盐在 mdrla/lb(-/-) 小鼠的肝脏和肾脏中产生比野生型小鼠更频繁和更严重的损伤。与野生型小鼠相比，mdrla/lb(-/-) 小鼠的血清丙氨酸氨基转移酶活性和血液尿素氮水平分别增加了 4 至 6 倍，分别表明肝和肾损伤。亚砷酸钠治疗 24 小时后，与野生型小鼠相比，mdrla/lb(-/-) 小鼠在肝脏（15.3 vs. 5.2 mug/g）、肾脏（7.23 vs. 3.22 mug/g）、小肠（3.98 vs 1.57 mug/g）和大脑（0.45 vs. 0.17 mug/g）中积累了更多的砷（14 mg/kg，皮下注射）给药。总之，这项研究表明，mdrla/lb(-/-) 小鼠对急性砷毒性更敏感，并且比野生型小鼠积累了更多的砷，这表明 P-糖蛋白至少部分参与哺乳动物的砷外流。 (C) 2002 Elsevier Science Ireland Ltd. 保留所有权利。
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.