Temperature dependent binding of mebendazole to tubulin in benzimidazole-susceptible and -resistant strains of Trichostrongylus colubriformis and Caenorhabditis elegans.
The binding of [3H]mebendazole ([3H]MBZ) to tubulin in benzimidazole-susceptible (BZ-S) and benzimidazole-resistant (BZ-R) strains of Trichostrongylus colubriformis and Caenorhabditis elegans was examined in order to investigate the biochemical changes to tubulin that result in BZ resistance in parasitic and free-living nematodes. In both species the extent of [3H]MBZ binding to tubulin was significantly reduced in the BZ-R strain compared with the BZ-S strain. The decrease in [3H]MBZ binding in the BZ-R strain of each species was the result of a significant reduction in the amount of charcoal stable [3H]MBZ-tubulin complexes and was not related to a change in the association constant of the [3H]MBZ-tubulin interaction. [3H]MBZ binding to tubulin was temperature dependent, reaching maximum levels at 37 degrees C in BZ-S T. colubriformis and 10 degrees C in BZ-R T. colubriformis. Both the BZ-S and BZ-R strains of C. elegans displayed maximum [3H]MBZ binding at 4 degrees C. Resistance ratios derived from the amount of [3H]MBZ binding in the BZ-S and BZ-R strains and in vitro development assays demonstrated that the temperature dependence and extent of drug binding was indicative of BZ resistance status and was species specific in the BZ-S isolates. These results indicate that biochemical differences exist in the binding of benzimidazole carbamates to tubulin in nematode species, and suggest that the susceptibility of the parasitic nematodes to the benzimidazole anthelmintics is the result of a unique high affinity and/or high capacity interaction of benzimidazole carbamates with tubulin.
Russell
G J
GJ
Department of Veterinary Pathology, University of Sydney, N.S.W., Australia.
Lacey
E
E
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002107:Caenorhabditis / Q000187:drug effects*; D004351:Drug Resistance; D008463:Mebendazole / Q000378:metabolism*; D013696:Temperature; D014254:Trichostrongylus / Q000187:drug effects*; D014404:Tubulin / Q000378:metabolism*
D001562:Benzimidazoles; D014404:Tubulin; D008463:Mebendazole