Hostname: page-component-848d4c4894-2pzkn Total loading time: 0 Render date: 2024-04-30T12:51:23.907Z Has data issue: false hasContentIssue false
  • English
  • Français

The metabolism of flubendazole and the activities of selected biotransformation enzymes in Haemonchus contortus strains susceptible and resistant to anthelmintics

Published online by Cambridge University Press:  01 May 2012

IVAN VOKŘÁL ,
HANA BÁRTÍKOVÁ ,
LUKÁŠ PRCHAL ,
LUCIE STUCHLÍKOVÁ ,
LENKA SKÁLOVÁ ,
BARBORA SZOTÁKOVÁ ,
JIŘÍ LAMKA ,
MARIÁN VÁRADY  and
VLADIMÍR KUBÍČEK
IVAN VOKŘÁL
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
HANA BÁRTÍKOVÁ
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
LUKÁŠ PRCHAL
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
LUCIE STUCHLÍKOVÁ
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
LENKA SKÁLOVÁ
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
BARBORA SZOTÁKOVÁ
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
JIŘÍ LAMKA
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
MARIÁN VÁRADY
Affiliation:
Institute of Parasitology, Slovak Academy of Sciences, Košice, Slovakia
VLADIMÍR KUBÍČEK*
Affiliation:
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic
*
*Corresponding author: Faculty of Pharmacy, Charles University, Heyrovského 1203, Hradec Králové, CZ-500 05Czech Republic. Tel: 00420 495 067 410. E-mail: kubicek@faf.cuni.cz
Get access Rights & Permissions [Opens in a new window]

Summary

Haemonchus contortus is one of the most pathogenic parasites of small ruminants (e.g. sheep and goat). The treatment of haemonchosis is complicated because of recurrent resistance of H. contortus to common anthelmintics. The aim of this study was to compare the metabolism of the anthelmintic drug flubendazole (FLU) and the activities of selected biotransformation enzymes towards model xenobiotics in 4 different strains of H. contortus: the ISE strain (susceptible to common anthelmintics), ISE-S (resistant to ivermectin), the BR strain (resistant to benzimidazole anthelmintics) and the WR strain (resistant to all common anthelmintics). H. contortus adults were collected from the abomasums from experimentally infected lambs. The in vitro as well as ex vivo experiments were performed and analysed using HPLC with spectrofluorimetric and mass-spectrometric detection. In all H. contortus strains, 4 different FLU metabolites were detected: FLU with a reduced carbonyl group (FLU-R), glucose conjugate of FLU-R and 2 glucose conjugates of FLU. In the resistant strains, the ex vivo formation of all FLU metabolites was significantly higher than in the susceptible ISE strain. The multi-resistant WR strain formed approximately 5 times more conjugates of FLU than the susceptible ISE strain. The in vitro data also showed significant differences in FLU metabolism, in the activities of UDP-glucosyltransferase and several carbonyl-reducing enzymes between the susceptible and resistant H. contortus strains. The altered activities of certain detoxifying enzymes might protect the parasites against the toxic effect of the drugs as well as contribute to drug-resistance in these parasites.

Keywords

UDP-glucosyltransferasecarbonyl reductasesstrain-differencesdrug metabolismhelminths
Type
Research Article
Information
Parasitology , Volume 139 , Issue 10 , September 2012 , pp. 1309 - 1316
Copyright
Copyright © Cambridge University Press 2012

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.)

References

REFERENCES

Alvarez, L. I., Solana, H. D., Mottier, M. L., Virkel, G. L., Fairweather, I. and Lanusse, C. E. (2005). Altered drug influx/efflux and enhanced metabolic activity in triclabendazole-resistant liver flukes. Parasitology 131, 501–510. doi: 10.1017/S0031182005007997 CrossRefGoogle ScholarPubMed
Alvinerie, M., Dupuy, J., Eeckhoutte, C., Sutra, J. F. and Kerboeuf, D. (2001). In vitro metabolism of moxidectin in Haemonchus contortus adult stages. Parasitology Research 87, 702–704. doi: 10.1007/s004360100408 CrossRefGoogle ScholarPubMed
Bártíková, H., Křížová, V., Lamka, J., Kubíček, V., Skálová, L., and Szotáková, B. (2010). Flubendazole metabolism and biotransformation enzymes activities in healthy sheep and sheep with haemonchosis. Journal of Veteterinary Pharmacology and Therapeutics 33, 56–62. doi: 10.1111/j.1365-2885.2009.01112.x CrossRefGoogle ScholarPubMed
Brennan, G. P., Fairweather, I., Trudgett, A., Hoey, E., McCoy, , McConville, M., Meaney, M., Robinson, M., McFerran, N., Ryan, L., Lanusse, C., Mottier, L., Alvarez, L., Solana, H., Virkel, G. and Brophy, P. M. (2007). Understanding triclabendazole resistance. Experimental and Molecular Pathology 82, 104–109. doi: 10.1016/j.yexmp.2007.01.009 CrossRefGoogle ScholarPubMed
Cvilink, V., Kubíček, V., Nobilis, M., Křížová, V., Szotáková, B., Lamka, J., Várady, M., Kuběnová, M., Novotná, R., Gavelová, M., Skálová, L. (2008 a). Biotransformation of flubendazole and selected model xenobiotics in Haemonchus contortus . Veterinary Parasitology 151, 242–248. doi: 10.1016/j.vetpar.2007.10.010 CrossRefGoogle ScholarPubMed
Cvilink, V., Lamka, J. and Skálová, L. (2009 a). Xenobiotic metabolizing enzymes and metabolism of anthelminthics in helminths. Drug Metabolism Reviews 41, 8–26. doi: 10.1080/03602530802602880 CrossRefGoogle ScholarPubMed
Cvilink, V., Skálová, L., Szotáková, B., Lamka, J., Kostiainen, R. and Ketola, R. A. (2008 b). LC-MS-MS identification of albendazole and flubendazole metabolites formed ex vivo by Haemonchus contortus . Analytical and Bioanalytical Chemistry 391, 337–343. doi: 10.1007/s00216-008-1863-9 CrossRefGoogle ScholarPubMed
Cvilink, V., Szotakova, B., Krizova, V., Lamka, J., and Skalova, L. (2009 b). Phase I biotransformation of albendazole in lancet fluke (Dicrocoelium dendriticum). Research in Veterinary Science 86, 49–55. doi: 10.1016/j.rvsc.2008.05.006 CrossRefGoogle ScholarPubMed
Cvilink, V., Szotáková, B., Vokřál, I., Bártíková, H., Lamka, J. and Skálová, L. (2009 c). Liquid chromatography/mass spectrometric identification of benzimidazole anthelminthics metabolites formed ex vivo by Dicrocoelium dendriticum . Rapid Communications in Mass Spectrometry 23, 2679–2684. doi: 10.1002/rcm.4170 CrossRefGoogle ScholarPubMed
Devine, C., Brennan, G. P., Lanusse, C. E., Alvarez, L. I., Trudgett, A., Hoey, E. and Fairweather, I. (2010 a). Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica . Parasitology Research 106, 1351–1363. doi: 10.1007/s00436-010-1806-1 CrossRefGoogle Scholar
Devine, C., Brennan, G. P., Lanusse, C. E., Alvarez, L. I., Trudgett, A., Hoey, E. and Fairweather, I. (2010 b). Enhancement of the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole. Parasitology Research 107, 337–353. doi: 10.1007/s00436-010-1866-2 CrossRefGoogle ScholarPubMed
Gonzalez-Covarrubias, V., Kalabus, J. L. and Blanco, J. G. (2008). Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER). Pharmaceutical Research 25, 1730–1734. doi: 10.1007/s11095-008-9592-5 CrossRefGoogle ScholarPubMed
Kotze, A. C. and McClure, S. J. (2001). Haemonchus contortus utilises catalase in defence against exogenous hydrogen peroxide in vitro . International Journal for Parasitology 31, 1563–1571. doi: 10.1016/S0020-7519(01)00303-4 CrossRefGoogle ScholarPubMed
Kubíček, V., Soukupová, M., Nobilis, M., Křížová, V., Szotáková, B, and Skálová, L. (2008). LC with fluorimetric detection for sensitive analysis of reduced flubendazole in biological samples. Chromatographia 68, 865–867. doi: 10.1365/s10337-008-0810-40009-5893/08/11 CrossRefGoogle Scholar
Maser, E. and Oppermann, U. C. (1997). Role of type-1 11beta-hydroxysteroid dehydrogenase in detoxification processes. European Journal of Biochemistry 249, 365–369. doi:10.1111/j.1432-1033.1997.00365.x CrossRefGoogle ScholarPubMed
Maté, L., Virkel, G., Lifschnitz, A., Ballent, M. and Lanusse, C. (2008). Hepatic and extra-hepatic metabolic pathways involved in flubendazole biotransformation in sheep. Biochemical Pharmacology 76, 773–783. doi: 10.1016/j.bcp.2008.07.002 CrossRefGoogle ScholarPubMed
Mizuma, T., Machida, M., Hayashi, M. and Awazu, S. (1982). Correlation of drug conjugative metabolism rates between in vivo and in vitro: glucuronidation and sulfation of p-nitrophenol as a model compound in rat. Journal of Pharmacobio-dynamics 5, 811–817.CrossRefGoogle Scholar
Mottier, L., Virkel, G., Solana, H., Alvarez, L., Salles, J. and Lanusse, C. (2004). Triclabendazole biotransformation and comparative diffusion of the parent drug and its oxidized metabolites into Fasciola hepatica . Xenobiotica 34, 1043–1057. doi: 10.1080/00498250400015285 CrossRefGoogle ScholarPubMed
Ohara, H., Miyabe, Y., Deyashiki, Y., Matsuura, K. and Hara, A. (1995). Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver. Biochemical Pharmacology 50, 221–227. doi: 10.1016/0006-2952(95)00124-I CrossRefGoogle ScholarPubMed
Palackal, N. T., Burczynski, M. E., Harvey, R. G. and Penning, T. M. (2001). Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1). Chemico-Biological Interactions 130–132, 815–824. doi: 10.1016/S0009-2797(00)00237-4 CrossRefGoogle ScholarPubMed
Robinson, M. W., Lawson, J., Trudgett, A., Hoey, E. M. and Fairweather, I. (2004). The comparative metabolism of triclabendazole sulphoxide by triclabendazole-susceptible and triclabendazole-resistant Fasciola hepatica . Parasitology Research 92, 205–210. doi: 10.1007/s00436-003-1003-6 CrossRefGoogle ScholarPubMed
Roos, M. H., Otsen, M., Hoekstra, R., Veenstra, J. G. and Lenstra, J. A. (2004). Genetic analysis of inbreeding of two strains of the parasitic nematode Haemonchus contortus . International Journal for Parasitology 34, 109–115. doi: 10.1016/j.ijpara.2003.10.002 CrossRefGoogle ScholarPubMed
Rothwell, J. and Sangster, N. (1997). Haemonchus contortus: the uptake and metabolism of closantel. International Journal for Parasitology 27, 313–319. doi: 10.1016/S0020-7519(96)00200-7 CrossRefGoogle ScholarPubMed
Solana, H. D., Rodriguez, J. A. and Lanusse, C. E. (2001). Comparative metabolism of albendazole and albendazole sulphoxide by different helminth parasites. Parasitology Research 87, 275–280. doi: 10.1007/PL00008578 CrossRefGoogle ScholarPubMed
Van Wyk, J. A. and Malan, F. S. (1988). Resistance of field strains of Haemonchus contortus to ivermectin, closantel, rafoxanide and the benzimidazoles in South Africa. Veterinary Record 123, 226–228. doi:10.1136/vr.123.9.226 CrossRefGoogle ScholarPubMed
Van Wyk, J. A., Gerber, H. M. and Groeneveld, H. T. (1980). A technique for recovery of nematodes from ruminants by migration from gastro-intestinal ingesta gelled in agar: large-scale application. Onderstepoort Journal of Veterinary Research 47, 147–158.Google ScholarPubMed