INVESTIGADORES
BALLENT Mariana
artículos
Título:
Hepatic and extra-hepatic metabolic phatways induced in flubendazole biotransformation in sheep
Autor/es:
MATÉ, L.; VIRKEL, G.; LIFSCHITZ, A.; BALLENT, M.; LANUSSE, C.
Revista:
BIOCHEMICAL PHARMACOLOGY
Editorial:
Elsevier
Referencias:
Año: 2008
ISSN:
0006-2952
Resumen:
Abstract
Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound used in pigs,
poultry and humans. Its potential for parasite control in ruminant species is under
investigation. The objective of the work described here was to identify the main enzymatic
pathways involved in the hepatic and extra-hepatic biotransformation of FLBZ in sheep.
Microsomal and cytosolic fractions obtained from sheep liver and duodenal mucosa
metabolised FLBZ into a reduced FLBZ metabolite (red- FLBZ). The keto-reduction of FLBZ
led to the prevalent (~98%) stereospecific formation of one enantiomeric form of red-FLBZ.
The amounts of red-FLBZ formed in liver subcellular fractions were 3 to 4-fold higher
(P<0.05) compared to those observed in duodenal subcellular fractions. This observation
correlates with the higher (P<0.05) carbonyl-reductase (CBR) activities measured in the liver
compared to the duodenal mucosa. No metabolic conversion was observed following FLBZ
or red-FLBZ incubation with sheep ruminal fluid. Sheep liver microsomes failed to convert
red-FLBZ into FLBZ. However, this metabolic reaction occurred in liver microsomes
prepared from phenobarbital-induced rats, which may indicate a cytochrome P450-mediated
oxidation of red-FLBZ. A NADPH-dependent CBR is proposed as the main enzymatic
system involved in the keto-reduction of FLBZ in sheep. CBR substrates such as menadione
and mebendazole (a non fluoride analogue of FLBZ), inhibited this liver microsomal
enzymatic reaction, which may confirm the involvement of a CBR enzyme in FLBZ
metabolism in sheep. This research is a further contribution to the understanding of the
metabolic fate of a promissory alternative compound for antiparasitic control in ruminant
species.
Keywords: flubendazole; biotransformation; microsomes; carbonyl reductase; sheepflubendazole; biotransformation; microsomes; carbonyl reductase; sheep