P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity
P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity
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DOI：
10.1006/taap.1996.8086
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发表时间：
1997-04-01
影响因子：
3.8
通讯作者：
Umbenhauer, D
中科院分区：
文献类型：
--
作者：
Lankas, GR;Cartwright, ME;Umbenhauer, D
CF-1小鼠亚群对阿维菌素、阿维菌素和伊维菌素的敏感性不同寻常，其神经毒性的发生剂量比其他物种和小鼠品系低100倍。我们已经证明，敏感的CF-I小鼠在肠上皮和脑毛细血管内皮中分别缺乏p -糖蛋白，这两个组织分别形成了渗透到体循环和中枢神经系统的主要屏障。与p -糖蛋白作为组织进入屏障的作用一致，敏感小鼠的血浆和组织中放射性标记伊维菌素的水平明显高于不敏感小鼠，特别是在毒性靶器官大脑中。不敏感的CF-1和cd -1小鼠在这些组织中显示出丰富的p糖蛋白水平，并且耐受阿维菌素剂量至少是敏感亚组最小毒性剂量的50倍。鉴于这些发现，在CF-1小鼠中同时使用阿维菌素和结构类似物伊维菌素（广泛用于治疗人类丝虫病，但没有证据表明其具有神经毒性），很可能这种存在于人脑内皮中的蛋白在人类中高度保守。(C) 1997学术出版社。
A subpopulation of CF-1 mice is unusual in its sensitivity to the avermectins, abamectin and ivermectin, with neurotoxicity occurring at 100-fold lower doses than in other species and mouse strains. We have shown that the sensitive CF-I mice are deficient in P-glycoprotein in the intestinal epithelium and brain capillary endothelium, tissues forming the principle barriers for penetration into the systemic circulation and central nervous system, respectively. Consistent with the role of P-glycoprotein as a barrier to tissue entry, the plasma and tissue levels of radiolabeled ivermectin in the sensitive mice were markedly higher than in the insensitive mice, particularly in brain, the target organ for toxicity. Insensitive CF-1 and CD-I mice showed abundant levels of P-glycoprotein in these tissues and tolerated doses of abamectin at least 50-fold the minimum toxic dose in the sensitive subgroup. In view of these findings in CF-1 mice with both abamectin and the structural analog ivermectin, which is used extensively in the treatment of human filariasis with no evidence of neurotoxicity, it is likely that this protein, found in human brain endothelium, is highly conserved in the human population. (C) 1997 Academic Press.