JAC Advance Access originally published online on July 15, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 180-187
© 2003 The British Society for Antimicrobial Chemotherapy
Modulation of the multidrug resistance (MDR) system in the nematode Haemonchus contortus by changing cholesterol content: effects on resistance to anthelmintics
1 Equipe Multi-résistances et Antiparasitaires; 2 Atelier scientifique commun de Cytométrie en flux, INRA-Tours: UR086-BioAgresseurs, Santé et Environnement, 37380 Nouzilly, France
Received 24 October 2002; returned 12 March 2003; revised 28 March 2003; accepted 18 May 2003
Objectives: The efficiency of the anthelmintics used to treat small domestic ruminants infected with nematodes is compromised by the emergence of resistant parasites. Both specific and non-specific mechanisms of resistance exist. The non-specific mechanisms involve multiple resistance phenomena and are dependent on the multidrug resistance (MDR) system, which is also responsible for the development of chemotherapy-resistant tumour cells. We showed previously that the system also exists in nematodes. Membrane ‘pumps’, known as P-glycoproteins (Pgp), are activated in the MDR system. The nature of the membrane, in particular the lipids, appears to condition the activity of the pumps. Thus, we studied the effects of cholesterol on drug transport activity in the nematode Haemonchus contortus.
Materials and methods: We used methyl-ß-cyclodextrin to carry out cholesterol depletion and cholesterol loading experiments. The resulting changes in resistance were estimated by measuring changes in drug transport (a) by means of in vitro egg hatch assays in the presence of a benzimidazole anthelmintic, thiabendazole and (b) by measuring the transport of rhodamine 123 (R123), a specific substrate of Pgp. We used biochemical assays to estimate the cholesterol concentration in the parasites.
Results: Changes in the cholesterol content induced changes in anthelmintic resistance; cholesterol depletion gave increased resistance and cholesterol loading gave decreased resistance. These changes also altered the transport of R123.
Conclusion: Cholesterol depletion or cholesterol loading allow modulation of xenobiotic resistance in nematode eggs as they do in tumour cells. The effect appears to be correlated with changes in the function of membrane P-glycoproteins. The lipid environment thus influences the nematode Pgp activity.
Keywords: P-glycoproteins, Haemonchus contortus, cholesterol, methyl-ß-cyclodextrin, thiabendazole
* Corresponding author. Tel: +33-2-47-42-77-53; Fax: +33-2-47-42-77-74; E-mail: kerboeuf{at}tours.inra.fr
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