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首页> 外文期刊>Archives of Toxicology >Potential impact of ABCB1 (p-glycoprotein) polymorphisms on avermectin toxicity in humans.
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Potential impact of ABCB1 (p-glycoprotein) polymorphisms on avermectin toxicity in humans.

机译:ABCB1(p-糖蛋白)多态性对人阿维菌素毒性的潜在影响。

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摘要

Several members of the ATP binding cassette (ABC) transporter protein superfamily perform xenobiotic efflux functions in mammals, limiting gut absorption, mediating excretion, and controlling entry of a wide range of chemicals to sensitive compartments such as brain, testes and foetus. Perhaps the best characterised of these is p-glycoprotein (gene name ABCB1/MDR1), a barrier epithelia expressed protein with structurally diverse substrates, including the avermectin pesticides. In specific mouse and dog strains, ABCB1 mutations have been identified that result in loss of p-glycoprotein function in the blood brain barrier (BBB) and increased susceptibility to avermectin neurotoxicity. As yet no large rearrangements of the human ABCB1 gene analogous to those in the mouse and dog have been identified. However, numerous human ABCB1 single nucleotide polymorphisms (SNPs) have been identified, the allelic frequencies of which vary with ethnicity. There is no clear consensus on whether or not SNPs, or combinations of SNPs, reduce human p-glycoprotein functionality. However, recent in vivo human data indicate that the two commonest ABCB1 haplotypes both exhibit full BBB functionality. We discuss here the role of p-glycoprotein in limiting brain absorption of avermectin pesticides, as well as the potential impact of the reported functional effects and population frequencies of known ABCB1 polymorphisms on avermectin pesticide risk assessments.
机译:ATP结合盒(ABC)转运蛋白超家族的几个成员在哺乳动物中执行异种外排功能,限制肠道吸收,介导排泄,并控制各种化学物质进入敏感区室(如大脑,睾丸和胎儿)。其中最有特色的也许是p-糖蛋白(基因名称ABCB1 / MDR1),它是一种屏障上皮表达的蛋白,具有结构多样的底物,包括阿维菌素农药。在特定的小鼠和狗品系中,已发现ABCB1突变会导致血脑屏障(BBB)中的p-糖蛋白功能丧失,并增加对阿维菌素神经毒性的敏感性。迄今为止,尚未鉴定出与小鼠和狗中的人相似的人ABCB1基因的大的重排。但是,已鉴定出许多人类ABCB1单核苷酸多态性(SNP),其等位基因频率随种族而变化。关于SNP或SNP的组合是否会降低人的p糖蛋白功能尚无明确共识。但是,最近的体内人类数据表明,两种最常见的ABCB1单倍型都具有完整的BBB功能。我们在这里讨论p-糖蛋白在限制阿维菌素农药对大脑的吸收中的作用,以及已知的ABCB1多态性对阿维菌素农药风险评估的功能效应和种群频率的潜在影响。

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