Prichard R K, Roulet A
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9.
Parasitology. 2007;134(Pt 8):1123-32. doi: 10.1017/S0031182007000091.
Macrocyclic lactones (MLs) are highly lipophilic anthelmintics which are known to bind to and open ligand-gated ion channels. However, these anthelmintics, and particularly the avermectin members of the ML class of endectocides, are potent substrates for ABC transporters and these transporters may regulate drug concentration in both the host and the parasite. There is accumulating evidence that ivermectin (IVM), and to a lesser extent moxidectin (MOX), selects for certain alleles of P-glycoprotein and other ABC transporter genes, selects for constitutive overexpression of some of these gene products, and induces overexpression of some P-glycoproteins in nematodes. However, such mechanisms of ML resistance do not easily lend themselves to the identification of SNP markers for resistance because of the diversity of ABC transporters in nematodes, the apparent diversity of effects of different MLs, and because regulatory elements for ABC transporter gene expression are not well understood in nematodes. Another non ligand-gated ion channel gene which appears to be under IVM selection, at least in Onchocerca volvulus and Haemonchus contortus, is beta-tubulin, and a simple genetic test for this selection has been described in O. volvulus. However, further work is required to elucidate a reliable marker associated with this gene in H. contortus or other parasitic nematodes of livestock. The possible involvement of ABC transporter genes and beta-tubulin in ML resistance provides a start in developing our understanding of this phenotype and markers for its detection in field populations of parasitic nematodes. However, more work is required before these leads can provide practical SNP markers for ML resistance.
大环内酯类药物（MLs）是高度亲脂性的驱虫剂，已知它们能与配体门控离子通道结合并使其开放。然而，这些驱虫剂，尤其是内寄生虫驱虫剂ML类中的阿维菌素成员，是ABC转运蛋白的有效底物，这些转运蛋白可能会调节宿主和寄生虫体内的药物浓度。越来越多的证据表明，伊维菌素（IVM），以及程度较轻的莫西菌素（MOX），会选择P-糖蛋白和其他ABC转运蛋白基因的某些等位基因，会导致其中一些基因产物的组成型过表达，并诱导线虫中某些P-糖蛋白的过表达。然而，由于线虫中ABC转运蛋白的多样性、不同MLs效应的明显差异，以及线虫中ABC转运蛋白基因表达的调控元件尚未完全了解，这种ML耐药机制不容易用于鉴定耐药性的单核苷酸多态性（SNP）标记。另一个似乎受到IVM选择的非配体门控离子通道基因是β-微管蛋白，至少在盘尾丝虫和捻转血矛线虫中是这样，并且在盘尾丝虫中已经描述了针对这种选择的简单基因检测方法。然而，需要进一步开展工作，以阐明与捻转血矛线虫或其他家畜寄生线虫中该基因相关的可靠标记。ABC转运蛋白基因和β-微管蛋白可能参与ML耐药性，这为我们开始了解这种表型及其在寄生线虫野外种群中检测的标记提供了一个起点。然而，在这些线索能够提供用于ML耐药性的实用SNP标记之前，还需要开展更多工作。
