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Effect of the metabolic inhibitor, methimazole on the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica

Published online by Cambridge University Press:  12 December 2008

C. DEVINE ,
G. P. BRENNAN ,
C. E. LANUSSE ,
L. I. ALVAREZ ,
A. TRUDGETT ,
E. HOEY  and
I. FAIRWEATHER
C. DEVINE
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
G. P. BRENNAN
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
C. E. LANUSSE
Affiliation:
Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000Tandil, Argentina
L. I. ALVAREZ
Affiliation:
Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000Tandil, Argentina
A. TRUDGETT
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
E. HOEY
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
I. FAIRWEATHER*
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
*
*Corresponding author: School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland. Tel: +44 28 90972298. Fax: +44 28 90975877. E-mail: i.fairweather@qub.ac.uk
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Summary

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) is altered in the presence of a metabolic inhibitor. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-sensitive isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 μm). Flukes were then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nm); MTZ+NADPH+TCBZ (15 μg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 μg/ml). Morphological changes resulting from drug treatment and following metabolic inhibition were assessed using scanning electron microscopy. After treatment with either TCBZ or TCBZ.SO alone, there was greater surface disruption to the triclabendazole-susceptible than -resistant isolate. However, co-incubation with MTZ and TCBZ/TCBZ.SO lead to more severe surface changes to the TCBZ-resistant isolate than with each drug on its own; this was not seen for the TCBZ-susceptible Cullompton isolate. Results of this study support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

Keywords

Fasciola hepaticaliver fluketriclabendazole resistancemethimazolescanning electron microscopy
Type
Research Article
Information
Parasitology , Volume 136 , Issue 2 , February 2009 , pp. 183 - 192
Copyright
Copyright © 2008 Cambridge University Press

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