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Relationships between sterol/phospholipid composition and xenobiotic transport in nematodes

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Abstract

Therapeutic failure limits prophylaxis of nematode diseases and has been mainly attributed to mutations in cellular targets of anthelmintics. Besides these specific mechanisms, alterations of drug transport also occur in parasites resistant to anthelmintics and depend on both the presence of membrane pumps such as P-glycoprotein (Pgp) and on the lipid composition of membranes. We recently showed in the nematode Haemonchus contortus, using eggs as a model, that the total cholesterol (TC) concentration alters the transport of lipophilic molecules due to membrane pumps such as P-glycoprotein and the resistance to anthelmintics. The effect of TC may depend on the presence of other lipids interacting with TC. Therefore, we analysed the lipid composition and its relationship with Pgp and resistance to anthelmintics. Better correlations were found between Pgp and free cholesterol (FC) than with TC. We also showed that the relationships between lipid composition and resistance to anthelmintics or Pgp depended on the equilibrium between FC and phospholipids (PLs), mainly PLs known to be present primarily in either the external leaflets of cell membranes or the internal leaflets. The PLs phosphatidylcholine and phosphatidylethanolamine played the most significant role, but phosphatidic acid also influenced drug resistance.

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Abbreviations

ABC:

ATP binding cassette

au:

arbitrary units

C elegans :

Caenorhabditis elegans

DPG:

diphosphoglycerids

FC:

free cholesterol

H contortus :

Haemonchus contortus

LC50:

50% lethal concentration

LPC:

lysophosphatidylcholine

Mabs:

monoclonal antibodies

MDR:

multidrug resistance

R123:

rhodamine 123

PA:

phosphatidic acid

PC:

phosphatidylcholine

PE:

phosphatidylethanolamine

Pgp:

P-glycoprotein

PI:

phosphatidylinositol

PL:

phospholipids

PS:

phosphatidylserine

SM:

sphingomyeline

TBZ:

thiabendazole

TC:

total cholesterol

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Acknowledgment

This work was financed by INRA and the Region Centre. We thank Dr. Yan Van Wyk, Dr. Gilles Aumont, and Professor Roger Prichard for kindly providing the H. contortus isolates, Mr. Limouzin and his team for the careful maintenance of the animals, and Marie-Colette Fauré and her team for their precious help with the references. The experiments comply with the current French laws.

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  1. Mickaël Riou

    Present address: IRBI, UMR CNRS 6035, Faculty of Sciences and Techniques, 37200, Tours, France

Authors and Affiliations

  1. Multiresistances and Antiparasitic Drugs, INRA: UR1282, Animal Infections and Public Heath, IASP, 37380, Nouzilly, France

    Mickaël Riou & Dominique Kerboeuf

  2. Quality of Gamets and Embryos, INRA: UR083 Poultry Research, 37380, Nouzilly, France

    Isabelle Grasseau & Elisabeth Blesbois

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  1. Mickaël Riou
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  2. Isabelle Grasseau
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  4. Dominique Kerboeuf
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Correspondence to Dominique Kerboeuf.

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Riou, M., Grasseau, I., Blesbois, E. et al. Relationships between sterol/phospholipid composition and xenobiotic transport in nematodes. Parasitol Res 100, 1125–1134 (2007). https://doi.org/10.1007/s00436-006-0455-x

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