INVESTIGADORES
ALVAREZ Luis Ignacio
artículos
Título:
Altered drug influx/efflux and enhanced metabolic activity in triclabendazole-resistant liver flukes
Autor/es:
ALVAREZ, L.; SOLANA, H.; MOTTIER, L.; VIRKEL, G.; FAIRWEATHER, I.; LANUSSE, C.
Revista:
PARASITOLOGY
Editorial:
CAMBRIDGE UNIV PRESS
Referencias:
Año: 2005 vol. 131 p. 501 - 510
ISSN:
0031-1820
Resumen:
Triclabendazole (TCBZ) is a halogenated benzimidazole compound that possesses high activity against immature and adultstages of the liver fluke, Fasciola hepatica. The intensive use of TCBZ in endemic areas of fascioliasis has resulted in thedevelopment of liver flukes resistant to this compound. TCBZ sulphoxide (TCBZSO) and TCBZ sulphone (TCBZSO2)are the main molecules recovered in the bloodstream of TCBZ-treated animals. In order to gain some insight into thepossible mechanisms of resistance to TCBZ, the goals of the work described here were: to compare the ex vivo transtegumentaldiffusion of TCBZ parent drug and its sulpho-metabolites (TCBZSO and TCBZSO2) into TCBZ-susceptibleand -resistant liver flukes; and to assess the comparative pattern of TCBZ biotransformation by TCBZ-susceptible and-resistant F. hepatica. For the tegumental diffusion studies, TCBZ-susceptible (Cullompton) and -resistant (Sligo) adultflukes collected from untreated infected sheep were incubated (15–180 min) in KRT buffer containing either TCBZ,TCBZSO or TCBZSO2 (5 nmol.mlx1). For the metabolism studies, microsomal fractions obtained from TCBZ-susceptibleand -resistant flukes were incubated for 60 min with TCBZ (40 mM), and the amount of the formed metabolic product(TCBZSO) was measured. Drug/metabolite concentrations were quantified by HPLC. All the assayed TCBZ-relatedmolecules penetrated through the tegument of both TCBZ-susceptible and -resistant flukes. However, significantly lower(approximately 50%) concentrations of TCBZ and TCBZSO were recovered within the TCBZ-resistant flukes comparedto the TCBZ-susceptible ones over the 180 min incubation period. The rate of TCBZ sulphoxidative metabolism intoTCBZSO was significantly higher (39%) in TCBZ-resistant flukes. The flavin-monooxigenase (FMO) enzyme systemappears to be the main metabolic pathway involved in the formation of TCBZSO in both TCBZ-susceptible and -resistantflukes. The altered drug influx/efflux and enhanced metabolic capacity identified in TCBZ-resistant liver flukes mayaccount for the development of resistance to TCBZ.