Abstract
The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3, cyp-6, cyp-7, cyp-8, UGT10B1, UGT24C1, UGT26A2, UGT365A1, UGT366C1, UGT368B2, UGT367A1, UGT371A1, UGT372A1 and pgp-3, pgp-9.1, pgp-9.2, pgp-10. This induction led to increased formation of ABZ metabolites (especially glycosides) and their increased export from the helminths’ body into the medium. The present study demonstrates for the first time that contact of H. contortus with sub-lethal doses of ABZ (e.g. during underdose treatment) improves the ability of H. contortus adults to deactivate ABZ in consequent therapy.
Highlights
Haemonchosis is one of the most important parasitic diseases of small ruminants
Transcriptional response of cytochrome P450 (CYP) to exposure to sub‐lethal concentrations of ABZ and ABZSO in H. contortus adults The expression levels of 8 individual CYPs (Wormbase ID numbers are listed in Additional file 1: Table S1) in control nematodes and in nematodes exposed to sub-lethal concentrations of ABZ and ABZSO for 4 and 12 h were analyzed and compared
The available concentration of anthelmintic basically depends on drug absorption, distribution, metabolism and elimination, any of which might vary due to several factors e.g. animal species, breed, age, weight, sex and nutrition [26, 27]
Summary
The nematode Haemonchus contortus (H. contortus), blood-feeding parasite in abomasum, has a broad range of host species, frequent and cosmopolitan geographic distribution, as well as a Kellerová et al Vet Res (2020) 51:94 decreases due to drug-resistance development in helminths, with the helminths’ high fertility and short generational interval providing an enviable developmental plasticity in terms of adaptation and the fast development of drug resistance in H. contortus [1]. Among the many mechanisms of drug resistance, some are based on the increased expression and activity of drug-metabolizing enzymes (DME) [5, 6]. These proteins protect all organisms against the potential negative action of drugs and other xenobiotics, which can be metabolized (in series or independently) by three processes, termed Phase I to Phase III. In Phase III, xenobiotics and/or their metabolites are transported across membranes to facilitate their biotransformation and elimination [6]
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