Albendazole enantiomeric metabolism and binding to cytosolic proteins in the liver fluke <Emphasis Type="Italic">Fasciola hepatica</Emphasis> |
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Authors: | H Solana S Scarcella G Virkel C Ceriani J Rodríguez C Lanusse |
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Institution: | (1) Lab. Biología Celular y Molecular, Dpto. de Cs. Biológicas, FCV-UNICEN, Campus Universitario, Tandil, Argentina;(2) Lab. de Farmacología, Dpto. de Fisiopatología. FCV-UNICEN, Campus Universitario, Tandil, Argentina |
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Abstract: | Fascioliasis causes important economic losses in ruminant species all over the world. Its control is largely based on the
use of the flukicidal compound triclabendazole (TCBZ). However, its chemically related benzimidazole anthelmintic albendazole
(ABZ) is being successfully used to control TCBZ-resistance flukes. This research gains some insights into the comparative
molecular behaviour of both anthelmintics within the target fluke. The goals of the current work were: (i) to assess the competitive
binding of ABZ and TCBZ to cytosolic proteins of F. hepatica, and (ii) to evaluate the enantioselective biotransformation of ABZ in microsomal fractions obtained from TCBZ-susceptible
and TCBZ-resistant strains of the liver fluke. Cytosolic proteins from fluke specimens bound TCBZ with greater affinity (83%)
than ABZ (44%) and the fraction of TCBZ bound to cytosolic proteins was not displaced by ABZ. The microsomes from both -susceptible
and resistant flukes sulphoxidized ABZ into ABZ sulphoxide (ABZSO). However, this oxidative activity was 49% higher in microsomes
from TCBZ-resistant flukes (P < 0.001) with a predominant production of the (+) ABZSO enantiomer. As earlier shown for TCBZ,
the results reported here confirm an enhanced ability for ABZ oxidation in TCBZ-resistant flukes. While this enhanced oxidative
metabolism of ABZ may cooperate to the resistance phenomenon, other pharmacodynamic-based mechanisms may be involved, which
would explain why, although being chemically-related, ABZ remains efficacious against TCBZ resistant flukes under field conditions. |
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Keywords: | Fasciola hepatica Albendazole Enantiomeric metabolism Binding to cytosolic proteins Triclabendazole resistance |
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