Albendazole enantiomeric metabolism and binding to cytosolic proteins in the liver fluke fasciola hepatica

SOLANA HD; SCARCELLA SILVANA; VIRKEL G; CERIANI MC; RODRIGUEZ JA; LANUSSE CE

VETERINARY RESEARCH COMMUNICATIONS

Springer Netherlands

Año: 2009 vol. 33 p. 163 - 173

0165-7380

Fascioliasis causes important economic losses in ruminant species all over theworld. Its control is largely based on the use of the flukicidal compound triclabendazole(TCBZ). However, its chemically related benzimidazole anthelmintic albendazole (ABZ) isbeing successfully used to control TCBZ-resistance flukes. This research gains someinsights into the comparative molecular behaviour of both anthelmintics within the targetfluke. The goals of the current work were: (i) to assess the competitive binding of ABZ andTCBZ to cytosolic proteins of F. hepatica, and (ii) to evaluate the enantioselectivebiotransformation of ABZ in microsomal fractions obtained from TCBZ-susceptible andTCBZ-resistant strains of the liver fluke. Cytosolic proteins from fluke specimens boundTCBZ with greater affinity (83%) than ABZ (44%) and the fraction of TCBZ bound tocytosolic proteins was not displaced by ABZ. The microsomes from both -susceptible andresistant flukes sulphoxidized ABZ into ABZ sulphoxide (ABZSO). However, thisoxidative 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-resistantflukes. While this enhanced oxidative metabolism of ABZ may cooperate to the resistancephenomenon, other pharmacodynamic-based mechanisms may be involved, which wouldexplain why, although being chemically-related, ABZ remains efficacious against TCBZresistant flukes under field conditions