Modulation of the multidrug resistance (MDR) system in the nematode Haemonchus contortus by changing cholesterol content: effects on resistance to anthelmintics.
OBJECTIVE
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.


METHODS
We used methyl-beta-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.


CONCLUSIONS
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.
Riou
Mickaël
M
Equipe Multi-résistances et Antiparasitaires, Santé et Environnement, Nouzilly, France.
Guégnard
Fabrice
F
Le Vern
Yves
Y
Kerboeuf
Dominique
D
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D000969:Antinematodal Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D006189:Haemonchus / Q000187:drug effects* / Q000378:metabolism*
D000871:Anthelmintics; D000969:Antinematodal Agents; D002784:Cholesterol