title: Albendazole enantiomeric metabolism and binding to cytosolic proteins in the liver fluke Fasciola hepatica.
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.
authors: Lab Biología Celular y Molecular, Dpto de Cs Biológicas, FCV-UNICEN, Campus Universitario, Tandil, Argentina. hsolana@vet.unicen.edu.ar
authors: H
authors: H
authors: Solana
authors: S
authors: S
authors: Scarcella
authors: G
authors: G
authors: Virkel
authors: C
authors: C
authors: Ceriani
authors: J
authors: J
authors: Rodríguez
authors: C
authors: C
authors: Lanusse
mesh_terms: D015766:Albendazole / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000378:metabolism*; D001562:Benzimidazoles / Q000378:metabolism*; D001667:Binding, Competitive / Q000502:physiology; D002850:Chromatography, Gel / Q000662:veterinary; D003600:Cytosol / Q000378:metabolism; D005210:Fasciola hepatica / Q000378:metabolism*; D005211:Fascioliasis / Q000469:parasitology / Q000662:veterinary*; D015801:Helminth Proteins / Q000378:metabolism*; D008109:Liver Diseases, Parasitic / Q000469:parasitology / Q000662:veterinary*; D008861:Microsomes / Q000378:metabolism; D011485:Protein Binding; D012756:Sheep; D012757:Sheep Diseases / Q000469:parasitology*; D013237:Stereoisomerism; D000077682:Triclabendazole
chemical_list: D000871:Anthelmintics; D001562:Benzimidazoles; D015801:Helminth Proteins; D000077682:Triclabendazole; D015766:Albendazole; C027186:albendazole sulfoxide