Hostname: page-component-89b8bd64d-mmrw7 Total loading time: 0 Render date: 2026-05-09T22:03:38.483Z Has data issue: false hasContentIssue false
  • English
  • Français

ABC transporters and β-tubulin in macrocyclic lactone resistance: prospects for marker development

Published online by Cambridge University Press:  03 July 2007

R. K. PRICHARD  and
A. ROULET
R. K. PRICHARD*
Affiliation:
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9
A. ROULET
Affiliation:
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9
*
*Corresponding author: Institute of Parasitology, McGill University, 21111 Lakeshore road, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9. Tel: +1-514-398-7729. Fax: +1-514-398-7857. E-mail: roger.prichard@mcgill.ca
Get access Rights & Permissions [Opens in a new window]

Summary

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 β-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 β-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.

Keywords

Macrocyclic lactone anthelminticsivermectinmoxidectindrug resistancenematodeABC transportersP-glycoproteinsβ-tubulin

Information

Type
Research Article
Information
Parasitology , Volume 134 , Special Issue 8: MARKERS FOR ANTHELMINTIC RESISTANCE , August 2007 , pp. 1123 - 1132
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

REFERENCES

Addiss, D. G., Beach, M. J., Streit, T. G., Lutwick, S., LeConte, F. H., Lafontant, H. G., Hightower, A. W. and Lammie, P. J. (1997). Randomised placebo-controlled comparison of ivermectin and albendazole alone and in combination for Wuchereria bancrofti microfilaraemia in Haitian children. Lancet 350, 480–484.CrossRefGoogle ScholarPubMed
Ali, M. M., Mukhtar, M. M., Baraka, O. Z., Homeida, M. M., Kheir, M. M. and Mackenzie, C. D. (2002). Immunocompetence may be important in the effectiveness of Mectizan (ivermectin) in the treatment of human onchocerciasis. Acta Tropica 84, 49–53.CrossRefGoogle ScholarPubMed
Ardelli, B. F., Guerriero, S. B. and Prichard, R. K. (2005). Genomic organization and effects of ivermectin selection on Onchocerca volvulus P-glycoprotein. Molecular and Biochemical Parasitology 143, 58–66.CrossRefGoogle ScholarPubMed
Ardelli, B. F., Guerriero, S. B. and Prichard, R. K. (2006 a). Ivermectin imposes selection pressure on P-glycoprotein from Onchocerca volvulus: linkage disequilibrium and genotype diversity. Parasitology 132, 375–386.CrossRefGoogle ScholarPubMed
Ardelli, B. F., Guerriero, S. B. and Prichard, R. K. (2006 b). Characterization of a half-size ATP-binding cassette transporter gene which may be a useful marker for ivermectin selection in Onchocerca volvulus. Molecular and Biochemical Parasitology 145, 94–100.CrossRefGoogle ScholarPubMed
Ardelli, B. F. and Prichard, R. K. (2004). Identification of variant ABC- transporter genes among Onchocerca volvulus collected from ivermectin-treated and untreated patients in Ghana, West Africa. Annals of Tropical Medicine and Parasitology 98, 371–384.CrossRefGoogle ScholarPubMed
Awadzi, K., Attah, S. K., Addy, E. T., Opoku, N. O., Quartey, B. T., Lazdins-Helds, J. K., Ahmed, K., Boatin, B. A., Boakye, D. A. and Edwards, G. (2004 b). Thirty-month follow-up of sub-optimal responders to multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Annals of Tropical Medicine and Parasitology 98, 359–370.CrossRefGoogle ScholarPubMed
Awadzi, K., Boakye, D. A., Edwards, G., Opoku, N. O., Attah, S. K., Osei-Atweneboana, M. Y., Lazdins-Helds, J. K., Ardrey, A. E., Addy, E. T., Quartey, B. T., Ahmed, K., Boatin, B. A. and Soumbey-Alley, E. W. (2004 a). An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Annals of Tropical Medicine and Parasitology 98, 231–249.CrossRefGoogle ScholarPubMed
Baraka, O. Z., Mahmoud, B. M., Marschke, C. K., Geary, T. G., Homeida, M. M. and Williams, J. F. (1996). Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus. European Journal of Clinical Pharmacology 50, 407–410.CrossRefGoogle ScholarPubMed
Bennett, J. L., Williams, J. F. and Dave, V. (1988). Pharmacology of ivermectin. Parasitology Today 4, 226–228.CrossRefGoogle ScholarPubMed
Blackhall, W., Liu, H. Y., Xu, M., Prichard, R. K. and Beech, R. N. (1998). Selection at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains of Haemonchus contortus. Molecular and Biochemical Parasitology 95, 193–201.CrossRefGoogle Scholar
Blair, L. S. and Campbell, W. C. (1980). Efficacy of ivermectin against Dirofilaria immitis larvae in dogs (31, 60 and 90 days after infection). American Journal of Veterinary Research 41, 2108.Google Scholar
Boatin, B. A., Hougard, J. M., Alley, E. S., Akpoboua, L. K., Yameogo, L., Dembele, N., Seketeli, A. and Dadzie, K. Y. (1998). The impact of Mectizan on the transmission of onchocerciasis. Annals of Tropical Medicine and Parasitology 92 Supp (S1), 46–60.CrossRefGoogle ScholarPubMed
Boersema, J. H., Eysker, M. and Nas, J. W. (2002). Apparent resistance of Parascaris equorum to macrocylic lactones. Veterinary Record 150, 279–281.CrossRefGoogle ScholarPubMed
Bourguinat, C., Pion, S. D. S., Kamgno, J., Gardon, J., Gardon-Wendel, N., Duke, B. O. L., Prichard, R. K. and Boussinesq, M. (2006). Genetic polymorphism of the β-tubulin gene of Onchocerca volvulus in ivermectin naïve patients from Cameroon, and its relationship with fertility of the worms. Parasitology 132, 255–262.CrossRefGoogle ScholarPubMed
Campbell, W. C. (1985). Ivermectin: an update. Parasitology Today 1, 10–16.CrossRefGoogle ScholarPubMed
Clark, J. M., Scott, J. G., Campos, F. and Bloomquist, J. R. (1995). Resistance to avermectins: extent, mechanisms, and management implications. Annual Review of Entomology 40, 1–30.CrossRefGoogle ScholarPubMed
Coles, G. C., Rhodes, A. C. and Wolstenholme, A. J. (2005). Rapid selection for ivermectin resistance in Haemonchus contortus. Veterinary Parasitology 129, 345–347.CrossRefGoogle ScholarPubMed
Cotreau, M. M., Warren, S., Ryan, J. L., Fleckenstein, L., Vanapalli, S. R., Brown, K. R., Rock, D., Chen, C. Y. and Schwertschlag, U. S. (2003). The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans. Journal of Clinical Pharmacology 43, 1108–1115.CrossRefGoogle ScholarPubMed
Cully, D. F., Vassilatis, D. K., Liu, K. K., Paress, P. S., Van der Ploeg, L. H., Schaeffer, J. M. and Arena, J. P. (1994). Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371, 707–711.CrossRefGoogle ScholarPubMed
Currie, B. J., Harumal, P., McKinnon, M. and Walton, S. F. (2004). First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei. Clinical Infectious Diseases 39, e8–12.CrossRefGoogle ScholarPubMed
Dent, J. A., Smith, M. M., Vassilatis, D. K. and Avery, L. (2000). The genetics of ivermectin resistance in Caenorhabditis elegans. Proceedings of the National Academy of Sciences, USA. 97, 2674–2679.CrossRefGoogle ScholarPubMed
Duke, B. O. L., Zea-Flores, G., Castro, J., Cupp, E. W. and Munoz, B. (1990). Effects of multiple monthly doses of ivermectin on adult Onchocerca volvulus. American Journal of Tropical Medicine and Hygiene 43, 657–664.CrossRefGoogle ScholarPubMed
Eng, J. K. L., Blackhall, W. J., Osei-Atweneboana, M. Y., Bourguinat, C., Galazzo, D., Beech, R. N., Unnasch, T. R., Awadzi, K., Lubega, G. W. and Prichard, R. K. (2006). Ivermectin selection on β-tubulin: Evidence in Onchocerca volvulus and Haemonchus contortus. Molecular and Biochemical Parasitology 150, 229–235.CrossRefGoogle ScholarPubMed
Eng, J. K. L. and Prichard, R. K. (2005). A comparison of genetic polymorphism in populations of Onchocerca volvulus from untreated- and ivermectin-treated patients. Molecular and Biochemical Parasitology 142, 193–202.CrossRefGoogle ScholarPubMed
Feng, X. P., Hayashi, J., Beech, R. N. and Prichard, R. K. (2002). Study of the nematode putative GABA type A receptor subunits: Evidence for modulation by ivermectin. Journal of Neurochemistry 83, 870–878.CrossRefGoogle ScholarPubMed
Freeman, A. S., Nghiem, C., Li, J., Ashton, F. T., Guerrero, J., Shoop, W. L. and Schad, G. A. (2003). Amphidial structure of ivermectin-resistant and -susceptible laboratory and field strains of Haemonchus contortus. Veterinary Parasitology 110, 217–226.CrossRefGoogle ScholarPubMed
Gardon, J., Boussinesq, M., Kamgno, J., Gardon-Wendel, N., Demanga-Ngangue, and Duke, B. O. L. (2002). Effects of standard and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomised controlled trial. Lancet 360, 203–210.CrossRefGoogle ScholarPubMed
Geary, T. M. (2005). Ivermectin 20 years on: maturation of a wonder drug. Trends in Parasitology 21, 530–532.CrossRefGoogle ScholarPubMed
Hearn, F. P. and Peregrine, A. S. (2003). Identification of foals infected with Parascaris equorum apparently resistant to ivermectin. Journal of the American Veterinary Medical Association 223, 482–485, 455.CrossRefGoogle ScholarPubMed
Huang, Y.-J. and Prichard, R. K. (1999). Identification and stage-specific expression of two putative P-glycoprotein coding genes in Onchocerca volvulus. Molecular and Biochemical Parasitology 102, 273–281.CrossRefGoogle ScholarPubMed
Humeres, E. C. and Morse, J. G. (2005). Baseline susceptibility of persea mite (Acari: Tetranychidae) to abamectin and milbemectin in avocado groves in Southern California. Experimental and Applied Acarology 36, 51–59.CrossRefGoogle ScholarPubMed
Kaplan, R. M. (2004). Drug resistance in nematodes of veterinary importance: a status report. Trends in Parasitology 20, 477–481.CrossRefGoogle ScholarPubMed
Kwa, M. S. G., Kooyman, F. N., Boersema, J. H. and Roos, M. H. (1993). Effect of selection for benzimidazole resistance in Haemonchus contortus on beta-tubulin isotype 1 and isotype 2 genes. Biochemical and Biophysical Research Communications 191, 413–419.CrossRefGoogle ScholarPubMed
Le Jambre, L. F., Lenane, I. J. and Wardrop, A. J. (1999). A hybridisation technique to identify anthelmintic resistance genes in Haemonchus. International Journal for Parasitology 29, 1979–1985.CrossRefGoogle ScholarPubMed
Lespine, A., Martin, S., Dupuy, J., Roulet, A., Pineau, T., Orlowski, S. and Alvinerie, M. (2007). Interaction of macrocyclic lactones with P-glycoprotein: Structure-affinity relationship. European Journal of Pharmaceutical Science 30, 84–94.CrossRefGoogle ScholarPubMed
Loveridge, B., McArthur, M., McKenna, P. B. and Mariadass, B. (2003). Probable multigeneric resistance to macrocyclic lactone anthelmintics in cattle in New Zealand. New Zealand Veterinary Journal 51, 139–141.CrossRefGoogle ScholarPubMed
McCall, J. W. (2005). The safety-net story about macrocyclic lactone heartworm preventives: a review, an update, and recommendations. Veterinary Parasitology 133, 197–206.CrossRefGoogle Scholar
Mealey, K. L., Bentjen, S. A., Gay, J. M. and Cantor, G. H. (2001). Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11, 727–733.CrossRefGoogle ScholarPubMed
Mejía, M. E., Fernández Igartúa, B. M., Schmidt, E. E. and Cabaret, J. (2003). Multispecies and multiple anthelmintic resistance on cattle nematodes in a farm in Argentina: the beginning of high resistance? Veterinary Research 34, 461–467.CrossRefGoogle Scholar
Molento, M. B., Lifschitz, A., Sallovitz, J., Lanusse, C. and Prichard, R. (2004). Influence of verapamil on the pharmacokinetics of the antiparasitic drugs ivermectin and moxidectin in sheep. Parasitology Research 92, 121–127.CrossRefGoogle ScholarPubMed
Molento, M. B. and Prichard, R. K. (1999). The effects of the multidrug-resistance-reversing agent verapamil and CL347,099 on the efficacy of ivermectin or moxidectin against unselected and drug-selected strains of Haemonchus contortus in jirds (Meriones unguiculatus). Parasitology Research 85, 1007–1011.CrossRefGoogle ScholarPubMed
Mu, J., Ferdig, M. T., Feng, X., Joy, D. A., Duan, J., Furuya, T., Subramanian, G., Aravind, L., Cooper, R. A., Wootton, J. C., Xiong, M. and Su, X. Z. (2003). Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Molecular Microbiology 49, 977–989.CrossRefGoogle ScholarPubMed
Njue, A. I., Hayashi, J., Kinne, L., Feng, X.-P. and Prichard, R. K. (2004). Mutations in the extracellular domains of glutamate-gated chloride channel α3 and β subunits from ivermectin-resistant Cooperia oncophora affect agonist sensitivity. Journal of Neurochemistry 89, 1137–1147.CrossRefGoogle ScholarPubMed
Osei-Atweneboana, M. Y., Eng, J. K. L., Boakye, D. A., Gyapong, J. O. and Prichard, R. K.Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two phase Epidemiological study. Lancet, in press.Google Scholar
Ottesen, E. A. (2006). Lymphatic filariasis: Treatment, control and elimination. Advances in Parasitology 61, 395–441.CrossRefGoogle ScholarPubMed
Pouliot, J. F., L'Heureux, F., Liu, Z., Prichard, R. K. and Georges, E. (1997). Ivermectin: Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Biochemical Pharmacology 53, 17–25.CrossRefGoogle ScholarPubMed
Prichard, R. K. (2001). Genetic variability following selection of Haemonchus contortus with anthelmintics. Trends in Parasitology 17, 445–453.CrossRefGoogle ScholarPubMed
Prichard, R. K. (2005). Is anthelmintic resistance a concern for heartworm control? What can we learn from the human filariasis control programs? Veterinary Parasitology 133, 243–253.CrossRefGoogle ScholarPubMed
Prichard, R. K., Steel, J. W., Lacey, E. and Hennessy, D. R. (1985). Pharmacokinetics of ivermectin in sheep following intravenous, intra-abomasal, or intraruminal administration. Journal of Veterinary Pharmacology and Therapeutics 8, 88–94.CrossRefGoogle ScholarPubMed
Przeworski, M. (2002). The signature of positive selection at randomly chosen loci. Genetics 160, 1179–1189.CrossRefGoogle ScholarPubMed
Roulet, A. and Prichard, R. K. (2006). Ivermectin and moxidectin cause constitutive and induced over expression of different P-glycoproteins in resistant Haemonchus contortus. Annual Meeting of the American Association of Veterinary Parasitologists, Honolulu, USA Abstract No 72.Google Scholar
Roulet, A., Puel, O., Gesta, S., Lepage, J. F., Drag, M., Soll, M., Alvinerie, M. and Pineau, T. (2003). MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. European Journal of Pharmacology 460, 85–91.CrossRefGoogle Scholar
Sangster, N. C., Bannan, S. C., Weiss, A. S., Nulf, S. C., Klein, R. D. and Geary, T. G. (1999). Haemonchus contortus: sequence heterogeneity of internucleotide binding domains from P-glycoproteins. Experimental Parasitology 91, 250–257.CrossRefGoogle ScholarPubMed
Schinkel, A. H., Smit, J. J., van Tellingen, O., Beijnen, J. H., Wagenaar, E., van Deemter, L., Mol, C. A., van der Valk, M. A., Robanus-Maandag, E. C., te Riele, H. P. et al. (1994). Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77, 491–502.CrossRefGoogle ScholarPubMed
Schulz-Key, H. (1990). Observations on the reproductive biology of Onchocerca volvulus. Acta Leiden 59, 27–44.Google ScholarPubMed
Schwab, A. E., Churcher, T. S., Schwab, A. J., Basáñez, M.-G. and Prichard, R. K. ( 2007). An analysis of the population genetics of potential multi-drug resistance in lymphatic filariasis due to combination chemotherapy. Parasitology. Feb. 26:1–16 [Epub ahead of print].CrossRefGoogle ScholarPubMed
Sheriff, J. C., Kotze, A. C., Sangster, N. C. and Hennessy, D. R. (2005). Effect of ivermectin on feeding by Haemonchus contortus in vivo. Veterinary Parasitology 128, 341–346.CrossRefGoogle ScholarPubMed
Shoop, W. L. (1993). Ivermectin resistance. Parasitology Today 9, 154–159.CrossRefGoogle ScholarPubMed
Strote, G., Bonow, I. and Attah, S. (1996). The ultrastructure of the anterior end of male Onchocerca volvulus: papillae, amphids, nerve ring and first indication of an excretory system in the adult filarial worm. Parasitology 113, 71–85.CrossRefGoogle ScholarPubMed
Tchakoute, V. L., Bronsvoort, M., Tanya, V., Renz, A. and Trees, A. J. (1999). Chemoprophylaxis of Onchocerca infections: in a controlled, prospective study ivermectin prevents calves becoming infected with O. ochengi. Parasitology 118, 195–199.CrossRefGoogle Scholar
Trawford, A. F., Burden, F. and Hodgkinson, J. (2005). Suspected moxidectin resistance in cyathostomes in two donkey herds at the Donkey Sanctuary, UK. Abstract of the 20th International Conference of the World Association for the Advancement of Veterinary Parasitology, Christchurch, New Zealand. Abstract No.196.Google Scholar
Wall, J. D., Andolfatto, P. and Przeworski, M. (2002). Testing models of selection and demography in Drosophila simulans. Genetics 162, 203–216.CrossRefGoogle ScholarPubMed
Wolstenholme, A. J., Fairweather, I., Prichard, R., von Samson-Himmelstjerna, G. and Sangster, N. C. (2004). Drug resistance in veterinary helminths. Trends in Parasitology 20, 469–476.CrossRefGoogle ScholarPubMed
Woodruff, H. B. and Burg, R. W. (1986). The antibiotics explosion. In Discoveries in Pharmacology (Volume 3). (Ed. Parnham, J. and Bruinvels, J.), pp. 338–341. Elsevier, The Netherlands.Google Scholar
Xu, M., Molento, M., Blackhall, W., Ribeiro, P., Beech, R. and Prichard, R. (1998). Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog. Molecular and Biochemical Parasitology 91, 327–335.CrossRefGoogle ScholarPubMed
Yates, D. M., Portillo, V. and Wolstenholme, A. J. (2003). The avermectin receptors of Haemonchus contortus and Caenorhabditis elegans. International Journal for Parasitology 33, 1183–1193.CrossRefGoogle ScholarPubMed