Abstract
The cattle tick Rhipicephalus microplus is one of the most important ectoparasites with great sanitary and economic impact for cattle rearing worldwide. Ivermectin is commonly used to control tick populations, but its use over the last 30 years has led to the development of resistant populations of R. microplus, and a concomitant loss of efficacy. In this context, we aimed to determine the metabolic mechanisms that contribute to ivermectin resistance in a resistant strain of this species. We performed lethal time bioassays with inhibitors of detoxifying enzymes and xenobiotic transporters (four detoxification pathways) using two strains of ticks: a susceptible strain, Mozo, and a resistant strain, Juarez. We used four inhibitors to test the involvement of different families of proteins responsible for detoxification of ivermectin, namely cytochrome P450, esterases, glutathione-S-transferase, and ATP Binding Cassette Transporters. We calculated the synergistic factor for each inhibitor and strain. To different degrees, all tested inhibitors altered the mortality rates in the strain Juarez, indicating that multiple mechanisms are responsible for the resistant phenotype. Detoxification mechanisms mediated by ABC transporters were observed to be the most important. Esterases, glutathione-S-transferases, and cytochrome-oxidases played less important roles in detoxification.
Highlights
Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) (Canestrini, 1887) is a tick species distributed in tropical and subtropical areas, including the Neotropical region in southern Africa and Asia
The resistance ratios (RR) of the Juarez strain was calculated from the LC50 and LC90 values, confirming the ivermectin resistance status of the Juarez strain (RR50 of 6.86 and a RR90 of 20.79) (Table 1)
Regression analyses obtained from the bioassays carried out with the larvae of Mozo strain in the presence of the inhibitors Piperonyl butoxide (PBO), DEF, and diethyl maleate (DEM) (Fig. 1) were used to calculate sublethal doses (LC5; CI 95%) for PBO, DEM, and DEF
Summary
Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) (Canestrini, 1887) is a tick species distributed in tropical and subtropical areas, including the Neotropical region in southern Africa and Asia. R. microplus is an important vector of the protozoan, Babesia spp., and the rickettsia species, Anaplasma marginale, which cause babesiosis and anaplasmosis, respectively. These infections result in a loss of productivity and are widespread in tropical and subtropical Latin American countries with high levels of humidity, including Brazil, Northern Argentina, Uruguay, Venezuela, Paraguay, Colombia, Bolivia, and the Caribbean region and Mexico[3]. The metabolic mechanisms of detoxification are mediated by enzyme families, including cytochrome P450, esterase, and glutathione-S-transferases. These enzymes oxidize, hydrolyse, and conjugate the substrate. We analysed the detoxification of ivermectin in both the strains using lethal time bioassays in the presence of inhibitors that block the enzymatic or transporter activity of the proteins under study, allowing the toxic effects of ivermectin to prevail, and, increase the mortality rate
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