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Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

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An Erratum to this article was published on 14 August 2011

An Erratum to this article was published on 14 August 2011

Abstract

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 μM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ + nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ + NADPH + TCBZ (15 μg/ml), or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO; 15 μg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ–resistant isolate. However, co-incubation with KTZ + TCBZ, but more particularly KTZ + TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: in the syncytium, for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

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Acknowledgements

This investigation was supported by a DARDNI Postgraduate Studentship to Catherine Devine. It was also partially supported by a grant from the European Union (DELIVER grant, no. FOOD-CT-200X-023025) and by a BBSRC/Defra grant (C00082X/1).

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  1. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen’s University of Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK

    C. Devine, G. P. Brennan, A. Trudgett, E. Hoey & I. Fairweather

  2. Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000, Tandil, Argentina

    C. E. Lanusse & L. I. Alvarez

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  1. C. Devine
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  2. G. P. Brennan
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Correspondence to I. Fairweather.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00436-011-2554-6

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Devine, C., Brennan, G.P., Lanusse, C.E. et al. Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica . Parasitol Res 109, 981–995 (2011). https://doi.org/10.1007/s00436-011-2304-9

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