title: Characterization of Haemonchus contortus P-glycoprotein-16 and its interaction with the macrocyclic lactone anthelmintics.
abstract: Anthelmintic resistance in veterinary nematodes, including Haemonchus contortus, has become a limitation to maintaining high standards of animal health. Resistance in this parasite, to all drug families including the macrocyclic lactones (MLs) is a serious issue worldwide. Mechanisms of resistance to the MLs appear to be complex and to include the elimination of these compounds by ABC transporter-like proteins present in nematodes. In order to investigate the potential involvement of ABC transporters in ML resistance in H. contortus, we have characterized the functionality of the ABC transporter H. contortus P-glycoprotein-16 (Hco-PGP-16) expressed in mammalian cells. This has included a study of its interaction with different MLs, including the avermectins, abamectin (ABA) and ivermectin (IVM), and the milbemycin, moxidectin (MOX). Hco-PGP-16 transport activity was studied using the fluorophore Rhodamine 123 (Rho 123). Transfected cells expressing Hco-PGP-16 accumulated less than 50% of Rho 123 than control cells, suggesting an active transport of this tracer dye by Hco-PGP-16. The influence of the MLs on the Rho123 transport by Hco-PGP-16 was then investigated. A marked inhibition of Rho123 transport by ABA and IVM was observed. In contrast, MOX showed less effect on inhibition of Rho123 transport by Hco-PGP-16, and the inhibition was not saturable. The difference in the interaction of the avermectins and MOX with Hco-PGP-16 may help explain the slower rate of development of resistance to MOX compared with the avermectins in H. contortus.
authors.affiliation: Institute of Parasitology, Macdonald Campus, McGill University, 21,111 Lakeshore Road, Ste-Anne-de-Bellevue, H9 X3V9 QC, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Godoy
authors.affiliation: Institute of Parasitology, Macdonald Campus, McGill University, 21,111 Lakeshore Road, Ste-Anne-de-Bellevue, H9 X3V9 QC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Che
authors.affiliation: Institute of Parasitology, Macdonald Campus, McGill University, 21,111 Lakeshore Road, Ste-Anne-de-Bellevue, H9 X3V9 QC, Canada.
authors.forename: R N
authors.initials: RN
authors.lastname: Beech
authors.affiliation: Institute of Parasitology, Macdonald Campus, McGill University, 21,111 Lakeshore Road, Ste-Anne-de-Bellevue, H9 X3V9 QC, Canada. Electronic address: roger.prichard@mcgill.ca.
authors.forename: R K
authors.initials: RK
authors.lastname: Prichard
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D005456:Fluorescent Dyes / Q000378:metabolism; D006189:Haemonchus / Q000187:drug effects* / Q000378:metabolism; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D018374:LLC-PK1 Cells; D018942:Macrolides / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D020112:Rhodamine 123 / Q000378:metabolism; D013552:Swine
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000969:Antinematodal Agents; D005456:Fluorescent Dyes; D015801:Helminth Proteins; D018942:Macrolides; D020112:Rhodamine 123
keywords: Abamectin; Ivermectin; Macrocyclic lactone resistance; Moxidectin; Nematode; P-glycoprotein