Hostname: page-component-84b7d79bbc-7nlkj Total loading time: 0 Render date: 2024-07-30T00:38:51.423Z Has data issue: false hasContentIssue false
  • English
  • Français

The activity of drug-metabolizing enzymes and the biotransformation of selected anthelmintics in the model tapeworm Hymenolepis diminuta

Published online by Cambridge University Press:  06 February 2012

HANA BÁRTÍKOVÁ ,
IVAN VOKŘÁL ,
LENKA SKÁLOVÁ ,
VLADIMÍR KUBÍČEK ,
JANA FIRBASOVÁ ,
DAVID BRIESTENSKÝ ,
JIŘÍ LAMKA  and
BARBORA SZOTÁKOVÁ
HANA BÁRTÍKOVÁ
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
IVAN VOKŘÁL
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
LENKA SKÁLOVÁ
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
VLADIMÍR KUBÍČEK
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
JANA FIRBASOVÁ
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
DAVID BRIESTENSKÝ
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
JIŘÍ LAMKA
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
BARBORA SZOTÁKOVÁ*
Affiliation:
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-50005 Hradec Králové, Czech Republic
*
*Corresponding author: Tel: +420 495 067 324. Fax: +420 495 067 168. E-mail: Barbora.Szotakova@faf.cuni.cz
Get access Rights & Permissions [Opens in a new window]

Summary

The drug-metabolizing enzymes of some helminths can deactivate anthelmintics and therefore partially protect helminths against these drugs' toxic effect. The aim of our study was to assess the activity of the main drug-metabolizing enzymes and evaluate the metabolism of selected anthelmintics (albendazole, flubendazole, mebendazole) in the rat tapeworm Hymenolepis diminuta, a species often used as a model tapeworm. In vitro and ex vivo experiments were performed. Metabolites of the anthelmintics were detected and identified by HPLC with spectrofluorometric or mass–spectrometric detection. The enzymes of H. diminuta are able to reduce the carbonyl group of flubendazole, mebendazole and several other xenobiotics. Although the activity of a number of oxidation enzymes was determined, no oxidative metabolites of albendazole were detected. Regarding conjugation enzymes, a high activity of glutathione S-transferase was observed. A methyl derivative of reduced flubendazole was the only conjugation metabolite identified in ex vivo incubations of H. diminuta with anthelmintics. The results revealed that H. diminuta metabolized flubendazole and mebendazole, but not albendazole. The biotransformation pathways found in H. diminuta differ from those described in Moniezia expanza and suggest the interspecies differences in drug metabolism not only among classes of helminths, but even among tapeworms.

Keywords

biotransformation enzymesdrug metabolismalbendazoleflubendazolemebendazoleliquid chromatography/mass spectrometry
Type
Research Article
Information
Parasitology , Volume 139 , Issue 6 , May 2012 , pp. 809 - 818
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

Barrett, J. (1997). Helminth detoxification mechanisms. Journal of Helminthology 71, 85–89.CrossRefGoogle ScholarPubMed
Barrett, J. (1998). Cytochrome P450 in parasitic protozoa and helminths. Comparative Biochemistry and Physiology 121, 181–183.Google ScholarPubMed
Bartikova, H., Krizova, V., Lamka, J., Kubicek, V., Skalova, L. and Szotakova, B. (2010 a). Flubendazole metabolism and biotransformation enzymes activities in healthy sheep and sheep with haemonchosis. Journal of Veteterinary Pharmacology and Therapeutics 33, 56–62.CrossRefGoogle ScholarPubMed
Bartikova, H., Vokral, I., Skalova, L., Lamka, J. and Szotakova, B. (2010 b). In vitro oxidative metabolism of xenobiotics in the lancet fluke (Dicrocoelium dendriticum) and the effects of albendazole and albendazole sulphoxide ex vivo. Xenobiotica 40, 593–601.CrossRefGoogle ScholarPubMed
Budke, C. M., Deplazes, P. and Torgerson, P. R. (2006). Global socioeconomic impact of cystic echinococcosis. Emerging Infectious diseases 12, 296–303.CrossRefGoogle ScholarPubMed
Cohen, R. and Mackey, K. (1977). Hymenolepis diminuta unresponsive to quinacrine. The Western Journal of Medicine 127, 340–341.Google ScholarPubMed
Cunningham, L. J. and Olson, P. D. (2010). Description of Hymenolepis microstoma (Nottingham strain): a classical tapeworm model for research in the genomic era. Parasites & Vectors 3, 123.CrossRefGoogle Scholar
Cvilink, V., Kubicek, V., Nobilis, M., Krizova, V., Szotakova, B., Lamka, J., Varady, M., Kubenova, M., Novotna, R., Gavelova, M. and Skálová, L. (2008 a). Biotransformation of flubendazole and selected model xenobiotics in Haemonchus contortus. Veterinary Parasitology 151, 242–248.CrossRefGoogle ScholarPubMed
Cvilink, V., Lamka, J. and Skalova, L. (2009 a). Xenobiotic metabolizing enzymes and metabolism of anthelminthics in helminths. Drug Metabolism Reviews 41, 8–26.CrossRefGoogle ScholarPubMed
Cvilink, V., Skalova, L., Szotakova, 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.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.CrossRefGoogle ScholarPubMed
Cvilink, V., Szotakova, B., Vokral, I., Bartikova, H., Lamka, J. and Skalova, 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.Google Scholar
Habig, W. H. and Jakoby, W. B. (1981). Glutathione S-transferases (rat and human). Methods in Enzymology 77, 218–231.CrossRefGoogle ScholarPubMed
Henkle-Duhrsen, K. and Kampkotter, A. (2001). Antioxidant enzyme families in parasitic nematodes. Molecular and Biochemical Parasitology 114, 129–142.Google Scholar
Hitchen, S. J., Shostak, A. W. and Belosevic, M. (2009). Hymenolepis diminuta (Cestoda) induces changes in expression of select genes of Tribolium confusum (Coleoptera). Parasitology Research 105, 875–879.Google Scholar
Horak, P. and Klimes, L. (2007). Helmintologie. In Paraziti a Jejich Biologie (ed. Volf, P. and Horák, P.), pp. 138–231. Triton, Praha, Czech Republic.Google Scholar
Hussain, M., Khan, I., Siddiqui, M., Farooq, M. and Ahmad, N. (2004). Prevalence of cestodes and comparative efficacy of various anthelmintics in Rambouillet sheep. International Journal of Agriculture and Biology 6, 1128–1131.Google Scholar
Jones, W. E. (1979). Niclosamide as a treatment for Hymenolepis diminuta and Dipylidium caninum infection in man. The American Journal of Tropical Medicine and Hygiene 28, 300–302.CrossRefGoogle ScholarPubMed
Kerboeuf, D., Soubieux, D., Guilluy, R., Brazier, J. L. and Riviere, J. L. (1995). In vivo metabolism of aminopyrine by the larvae of the helminth Heligmosomoides polygyrus. Parasitology Research 81, 302–304.Google Scholar
Kotze, A. C. (1997). Cytochrome P450 monooxygenase activity in Haemonchus contortus (Nematoda). International Journal for Parasitology 27, 33–40.CrossRefGoogle ScholarPubMed
Kotze, A. C., Dobson, R. J. and Chandler, D. (2006). Synergism of rotenone by piperonyl butoxide in Haemonchus contortus and Trichostrongylus colubriformis in vitro: potential for drug-synergism through inhibition of nematode oxidative detoxification pathways. Veterinary Parasitology 136, 275–282.Google Scholar
Kuntz, A. N., Davioud-Charvet, E., Sayed, A. A., Califf, L. L., Dessolin, J., Arner, E. S. J. and Williams, D. L. (2007). Thioredoxin glutathione reductase from Schistosoma mansoni: An essential parasite enzyme and a key drug target. PLoS Medicine 4, 1071–1086.Google Scholar
Maki, J. and Yanagisawa, T. (1985). Anthelmintic effects of bithionol, paromomycin sulphate, flubendazole and mebendazole on mature and immature Hymenolepis nana in mice. Journal of Helminthology 59, 211–216.CrossRefGoogle ScholarPubMed
Marangi, M., Zechini, B., Fileti, A., Quaranta, G. and Aceti, A. (2003). Hymenolepis diminuta infection in a child living in the urban area of Rome, Italy. Journal of Clinical Microbiology 41, 3994–3995.CrossRefGoogle Scholar
Maser, E. (1995). Xenobiotic carbonyl reduction and physiological steroid oxidoreduction – the pluripotency of several hydroxysteroid dehydrogenases. Biochemical Pharmacology 49, 421–440.CrossRefGoogle ScholarPubMed
Maté, L., Virkel, G., Lifschitz, A., Ballent, M. and Lanusse, C. (2008). Hepatic and extrahepatic metabolic pathways involved in flubendazole biotransformation in sheep. Biochemical Pharmacology 76, 773–783.CrossRefGoogle ScholarPubMed
Matossian, R. M., Rickard, M. D. and Smyth, J. D. (1977). Hydatidosis: a global problem of increasing importance. Bulletin of the World Health Organization 55, 499–507.Google ScholarPubMed
McCracken, R. O. and Taylor, D. D. (1983). Biochemical effects of thiabendazole and cambendazole on Hymenolepis diminuta (Cestoda) in vivo. Journal of Parasitology 69, 295–301.Google Scholar
McCracken, R. O., Lipkowitz, K. B. and Dronen, N. O. (1992). Efficacy of albendazole and mebendazole against Hymenolepis microstoma and Hymenolepis diminuta. Parasitology Research 78, 108–111.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.Google Scholar
Moreno, L., Alvarez, L., Mottier, L., Virkel, G., Bruni, S. S. and Lanusse, C. (2004). Integrated pharmacological assessment of flubendazole potential for use in sheep: disposition kinetics, liver metabolism and parasite diffusion ability. Journal of Veteterinary Pharmacology and Therapeutics 27, 299–308.CrossRefGoogle ScholarPubMed
Moro, P. L., Budke, C. M., Schantz, P. M., Vasquez, J., Santivanez, S. J. and Villavicencio, J. (2011). Economic impact of cystic echinococcosis in Peru. PLoS Neglected Tropical Diseases 5 (5), e1179.Google Scholar
Muller, R. and Wakelin, D. (2002). The cestodes. In Worms and Human Disease (ed. Muller, R.), pp. 63–105. CABI Publishing, New York, USA.Google Scholar
Munir, W. A. and Barrett, J. (1985). The metabolism of xenobiotic compounds by Hymenolepis diminuta (Cestoda: Cyclophyllidea). Parasitology 91, 145–156.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Ostlind, D. A., Mickle, W. G., Smith, S. K., Cifelli, S. and Ewanciw, D. V. (2004). The Hymenolepis diminuta-golden hamster (Mesocricetus auratus) model for the evaluation of gastrointestinal anticestode activity. Journal of Parasitology 90, 898–899.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.Google Scholar
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.CrossRefGoogle ScholarPubMed
Rossjohn, J., Feil, S. C., Wilce, M. C., Sexton, J. L., Spithill, T. W. and Parker, M. W. (1997). Crystallization, structural determination and analysis of a novel parasite vaccine candidate: Fasciola hepatica glutathione S-transferase. Journal of Molecular Biology 273, 857–872.Google Scholar
Saeed, H. M., Mostafa, M. H., O'Connor, P. J., Rafferty, J. A. and Doenhoff, M. J. (2002). Evidence for the presence of active cytochrome P450 systems in Schistosoma mansoni and Schistosoma haematobium adult worms. FEBS Letters 519, 205–209.Google Scholar
Salinas, G., Selkirk, M. E., Chalar, C., Maizels, R. M. and Fernandez, C. (2004). Linked thioredoxin-glutathione systems in platyhelminths. Trends in Parasitology 20, 340–346.CrossRefGoogle ScholarPubMed
Slocombe, J. O. D. (1979). Prevalence and treatment of tapeworms in horses. The Canadian Veterinary Journal 20, 136–140.Google Scholar
Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J. and Klenk, D. C. (1985). Measurement of protein using bicinchoninic acid. Analytical Biochemistry 150, 76–85.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.Google Scholar
Szotakova, B., Skalova, L., Wsol, V. and Kvasnickova, E. (2000). Reduction of the potential anticancer drug oracin in the rat liver in vitro. Journal of Pharmacy and Pharmacology 52, 495–500.CrossRefGoogle ScholarPubMed
Tanowitz, H. B., Weiss, L. M. and Wittner, M. (1993). Diagnosis and treatment of intestinal helminths. I. Common intestinal cestodes. Gastroenterologist 1, 265–273.Google Scholar
Webbe, G. (1994). Human cysticercosis: parasitology, pathology, clinical manifestations and available treatment. Pharmacology Therapeutics 64, 175–200.Google Scholar
White, A. C. (2000). Neurocysticercosis: Updates on epidemiology, pathogenesis, diagnosis, and management. Annual Review of Medicine 51, 187–206.Google Scholar
Wiwanitkit, V. (2004). Overview of Hymenolepis diminuta infection among Thai patients. Medscape General Medicine 6, 7.Google Scholar
Wsol, V., Szotakova, B., Martin, H. J. and Maser, E. (2007). Aldo-keto reductases (AKR) from the AKR1C subfamily catalyze the carbonyl reduction of the novel anticancer drug oracin in man. Toxicology 238, 111–118.Google Scholar
Wsol, V., Szotakova, B., Skalova, L. and Maser, E. (2004). The novel anticancer drug oracin: different stereospecificity and cooperativity for carbonyl reduction by purified human liver 11beta-hydroxysteroid dehydrogenase type 1. Toxicology 197, 253–261.CrossRefGoogle ScholarPubMed