Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica Parasitology

DEVINE, C.; BRENNAN, G.; LANUSSE, C.;¸ALVAREZ, L.; TRUDGETT, A.; HOEY, E.; FAIRWEATHER, I.

PARASITOLOGY RESEARCH

SPRINGER

Año: 2010 vol. 106 p. 1351 - 1358

0932-0113

A study has been carried out to investigate whetherthe action of triclabendazole (TCBZ) against Fasciolahepatica is altered by inhibition of drug metabolism. Theflavin monooxygenase system (FMO) was inhibited usingmethimazole (MTZ) to see whether a TCBZ-resistant isolatecould be made more sensitive to TCBZ action. The OberonTCBZ-resistant and Cullompton TCBZ-susceptible isolateswere used for these experiments. The FMO system wasinhibited by a 2-h pre-incubation in methimazole (100 μM),then incubated for a further 22 h in NCTC medium containingeither 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). Changes to fluke ultrastructure following drugtreatment and metabolic inhibition were assessed usingtransmission electron microscopy. After treatment with eitherTCBZ or TCBZ.SO on their own, there was greater disruptionto the TCBZ-susceptible than triclabedazole-resistant isolate.However, co-incubation with MTZ+TCBZ, but more particularlyMTZ+TCBZ.SO, led to more severe changes to theTCBZ-resistant isolate than with each drug on its own, withsevere swelling of the basal infolds and mucopolysaccharidemasses in the syncytium, accompanied by a reduction innumbers of secretory bodies. The synthesis and production ofsecretory bodies in the tegumental cells was severely affectedas well.With the TCBZ-susceptible Cullompton isolate, therewas limited potentiation of drug action. The results support theconcept of altered drug metabolism in TCBZ-resistant flukes,and this process may play a role in the development of drugresistance.