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

Catherine G. Devine, Gerard Brennan, C.E. Lanusse, L.I. Alvarez, Alan Trudgett, Elizabeth Hoey, Ian Fairweather

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

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 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 mu M). 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 mu g/ml); or PB + NADPH + TCBZ.SO (15 mu g/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.
Original languageEnglish
Pages (from-to)871-880
Number of pages10
JournalParasitology
Volume137
Issue number5
DOIs
Publication statusPublished - Apr 2010

ASJC Scopus subject areas

  • Animal Science and Zoology
  • Parasitology
  • Infectious Diseases

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