Selection at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains of Haemonchus contortus.
Resistance to anthelmintics that are used to control parasite populations in domestic animals has become a serious problem worldwide. The development of resistance is an evolutionary process that leads to genetic changes in parasite populations in response to drug exposure. The anthelmintic ivermectin is known to bind to the human membrane transport protein, P-glycoprotein, and P-glycoprotein-deficient mice treated with ivermectin have shown signs of neurotoxicity. P-glycoprotein is believed to be involved in the multidrug resistance phenotype seen in some human cancers and for drug resistance in some protists. We have examined the genetic variation of a P-glycoprotein homologue from the nematode Haemonchus contortus to see if an association exists between specific alleles of this gene and survival to exposure to ivermectin or moxidectin. Two parasite strains passaged without drug treatment and three strains, subjected to anthelmintic selection and derived from the unselected strains, were examined. Allelic variation in the unselected strains showed this locus to be highly polymorphic. chi 2 analyses of allele frequencies showed significant differences between the unselected and the drug-selected derived strains. In all three drug-selected strains, an apparent selection for the same allele was observed. These findings suggest that P-glycoprotein may be involved in resistance to both ivermectin and moxidectin in H. contortus.
Blackhall
W J
WJ
Institute of Parasitology, McGill University, Ste.-Anne-de-Bellevue, Quebec, Canada.
Liu
H Y
HY
Xu
M
M
Prichard
R K
RK
Beech
R N
RN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000483:Alleles; D000818:Animals; D000900:Anti-Bacterial Agents; D000969:Antinematodal Agents / Q000494:pharmacology*; D018509:DNA, Helminth / Q000032:analysis / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005787:Gene Frequency; D017238:Genes, Helminth; D014644:Genetic Variation; D006189:Haemonchus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007559:Ivermectin / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012641:Selection, Genetic; D013045:Species Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000969:Antinematodal Agents; D018509:DNA, Helminth; D018942:Macrolides; D007559:Ivermectin; C027837:moxidectin