Inhibition of cytochrome P450-mediated metabolism enhances ex vivo susceptibility of Fasciola hepatica to triclabendazole.

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

PARASITOLOGY

CAMBRIDGE UNIV PRESS

Año: 2010 vol. 137 p. 871 - 880

0031-1820

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is alteredby inhibition of drug metabolism. The cytochrome P450 (CYP P450) system was inhibited using piperonyl butoxide (PB).The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP P450system was inhibited by a 2 h pre-incubation in PB (100 mM). Flukes were then incubated for a further 22 h inNCTC medium containing either PB; PB+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM) ; PB+NADPH+TCBZ (15 mg/ml); or PB+NADPH+TCBZ.SO (15 mg/ml). Morphological changes resulting from drugtreatment and following metabolic inhibition were assessed using scanning electron microscopy. After treatment witheither TCBZ or TCBZ.SO alone, there was greater disruption to the TCBZ-susceptible than the resistant isolate.However, co-incubation with PB and TCBZ/TCBZ.SO lead to more severe surface changes to the TCBZ-resistant Oberonisolate than with each drug on its own. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation ofdrug action, and only with TCBZ.SO. The results support the concept of altered drug metabolism in TCBZ-resistantflukes and this process may play a role in the development of drug resistance.