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

• Published in: Parasitology Vol. 137; no. 5; pp. 871 - 880
• Main Authors: DEVINE, C., BRENNAN, G. P., LANUSSE, C. E., ALVAREZ, L. I., TRUDGETT, A., HOEY, E., FAIRWEATHER, I.
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.04.2010
• Subjects: Animals; Biological and medical sciences; Cytochrome; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Drug resistance; Enzyme Inhibitors - pharmacology; Fasciola hepatica; Fasciola hepatica - drug effects; Fasciola hepatica - enzymology; Fasciola hepatica - metabolism; Fasciola hepatica - ultrastructure; Fascioliasis - drug therapy; Fascioliasis - parasitology; Fundamental and applied biological sciences. Psychology; General aspects; General aspects and techniques. Study of several systematic groups. Models; Invertebrates; Liver Diseases, Parasitic - drug therapy; Liver Diseases, Parasitic - parasitology; liver fluke; Microscopy, Electron, Scanning; piperonyl butoxide; Piperonyl Butoxide - pharmacology; scanning electron microscopy; triclabendazole resistance; scanning electron microscopy; Fasciola hepatica; liver fluke; piperonyl butoxide; triclabendazole resistance; Scanning electron microscopy; Triclabendazole; Cytochrome P450; Liver; Plathelmintha; Parasite; Piperonyl butoxide; Metabolism; Trematoda; Sensitivity resistance; Ex vivo; Helmintha; Inhibition; Invertebrata
• ISSN: 0031-1820; 1469-8161
• DOI: 10.1017/S003118200999148X

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 P450) system was inhibited using piperonyl butoxide (PB). The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP P450 system was inhibited by a 2 h pre-incubation in PB (100 μm). Flukes were then incubated for a further 22 h in NCTC medium containing either PB; PB+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nm); PB+NADPH+TCBZ (15 μg/ml); or PB+NADPH+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 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 Oberon isolate than with each drug on its own. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action, and only with TCBZ.SO. 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.