INVESTIGADORES
LANUSSE Carlos Edmundo
artículos
Título:
Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica.
Autor/es:
DEVINE C; BRENNAN G; LANUSSE, C; ALVAREZ, L; TRUDGETT E.; HOEY E; FAIRWEATHER I
Revista:
PARASITOLOGY RESEARCH
Editorial:
SPRINGER
Referencias:
Lugar: Berlin; Año: 2011 p. 981 - 995
ISSN:
0932-0113
Resumen:
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 450) enzyme pathway was inhibited
using ketoconazole (KTZ) to see whether a TCBZ-resistant
isolate could be made more sensitive to TCBZ action. The
Oberon TCBZ-resistant and Cullompton TCBZ-susceptible
isolates were used for these experiments. The CYP 450
system was inhibited by a 2-h pre-incubation in ketoconazole
(40 μM), then incubated for a further 22 h in NCTC
medium containing either KTZ, KTZ+nicotinamide adenine
dinucleotide phosphate (NADPH) (1 nM), KTZ+NADPH+
TCBZ (15 μg/ml), or KTZ+NADPH+triclabendazole sulphoxide
(TCBZ.SO; 15 μg/ml). Changes to fluke ultrastructure
following drug treatment and metabolic inhibition were
assessed using transmission electron microscopy. After
treatment with either TCBZ or TCBZ.SO on their own,
there was greater disruption to the TCBZ-susceptible than
TCBZresistant isolate. However, co-incubation with KTZ+
TCBZ, but more particularly KTZ+TCBZ.SO, led to more
severe changes to the TCBZ-resistant isolate than with each
drug on its own: in the syncytium, for example, there was
severe swelling of the basal infolds and their associated
mucopolysaccharide masses, accompanied by an accumulation
of secretory bodies just below the apex. Golgi
complexes were greatly reduced or absent in the tegumental
cells and the synthesis, production, and transport of secretory
bodies were badly disrupted. With the TCBZ-susceptible
Cullompton isolate, there was limited potentiation of drug
action. 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.