A possible biochemical mode of action for benzimidazole anthelmintics

Abstract

Albendazole (ABZ), cambendazole (CBZ), oxibendazole (OBZ), and thiabendazole (TBZ) are potent, orally active, broad spectrum anthelmintics widely used in human and veterinary medicine. As members of the benzimidazole series, they are closely related chemically, and it is likely that they exert their anthelmintic effects in an identical fashion. We have examined the effects of these anthelmintics on the electrical resistance of planar bimolecular lipid membranes and compared the results with those obtained with a known uncoupler, 2,4-dinitrophenol (2,4-DNP). All drugs tested markedly reduced membrane resistance at concentrations lower than 0.1 μ m and were better proton conductors than 2,4-DNP by at least an order of magnitude. The sequence of proton conducting efficiency was ABZ > OBZ > TBZ > CBZ > 2,4-DNP. From 1 to 40 μ m, ABZ and CBZ substantially decreased P/0 (phosphorous/oxygen) ratios in coupled rat liver mitochondria in a concentration-dependent fashion using β-hydroxybutyrate as the substrate. 2,4-DNP was also shown to decrease P/0 ratios, but less effectively than the benzimidazole anthelmintics. These experiments indicate that the benzimidazole anthelmintics are lipid-soluble proton conductors that are effective in artificial (phospholipid bilayer) and natural (rat liver mitochondria) membrane systems. Dissipation of the transmembrane proton gradient should result in diminished levels of cellular ATP. In vivo treatment with a therapeutically effective dose of ABZ caused a severe disturbance in the energy balance of Hymenolepis diminuta; this was evident from a distinct drop in ATP levels, and from a decline in the ATP/ADP ratios, adenylate energy charge (AEC) and available adenylate energy (AAE) values. From these in vitro and in vivo experiments we conclude that benzimidazole anthelmintic activity, in part, may be due to bioenergetic disruptions resulting from transmembrane proton discharge.