title: ABC transporters and beta-tubulin in macrocyclic lactone resistance: prospects for marker development.
abstract: 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.
authors.affiliation: Institute of Parasitology, McGill University, 21111 Lakeshore Road, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9. goger.prichard@mcgill.ca
authors.forename: R K
authors.initials: RK
authors.lastname: Prichard
authors.forename: A
authors.initials: A
authors.lastname: Roulet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D015415:Biomarkers; D004351:Drug Resistance; D006376:Helminths / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D010802:Phylogeny; D014404:Tubulin / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000871:Anthelmintics; D015415:Biomarkers; D007783:Lactones; D047028:Macrocyclic Compounds; D014404:Tubulin