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

Abstract

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 microM). 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 microg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 microg/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.

Electron microscopical study to assess thein vitroeffects of the synthetic trioxolane OZ78 against the liver fluke,Fasciola hepatica

“…Female Wistar rats (purchased from RCC, Itingen, Switzerland) were experimentally infected with metacercarial cysts of the Cullompton isolate, shown in previous experiments to be susceptible to TCBZ in vivo and to its sulphoxide metabolite in vitro (Robinson et al 2002 ;McCoy et al 2005 ;Halferty et al 2008Halferty et al , 2009McConville et al 2006McConville et al , 2009Meaney et al 2006Meaney et al , 2007Devine et al 2009 ;Toner et al 2009). All animals were housed in environmentally-controlled conditions in groups of 4 and afforded 1 week to acclimatize.…”

Fasciola hepatica: disruption of spermatogenesis by the fasciolicide compound alpha

“…T tegument. Bar 200 μm b (Co. Devon, England) and has been shown to be susceptible to the action of TCBZ in vivo and to its sulphoxide metabolite in vitro (Robinson et al 2002;McCoy et al 2005;Meaney et al 2006Meaney et al , 2007Halferty et al 2008Halferty et al , 2009Devine et al 2009Devine et al , 2010McConville et al 2006McConville et al , 2009aToner et al 2009a, b).…”

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

“…The FMO system represents the main metabolic pathway for the metabolism of TCBZ to triclabendazole sulphoxide (TCBZ.SO) by F. hepatica (Alvarez et al 2005). A previous scanning electron microscopical study showed that inhibition of this system by methimazole (MTZ) leads to more severe surface changes in a TCBZresistant isolate when incubated with TCBZ and TCBZ.SO than when incubated in the drug alone (Devine et al 2009). More significantly, this potentiation of drug action by MTZ was not seen in a TCBZ-susceptible isolate.…”