Biotransformation of albendazole and activities of selected detoxification enzymes in Haemonchus contortus strains susceptible and resistant to anthelmintics

Vokřál, Ivan; Jirásko, Robert; Stuchlíková, Lucie Raisová; Bártíková, Hana; Szotáková, Barbora; Lamka, J.; Várady, Marián; Skálová, Lenka

doi:10.1016/j.vetpar.2013.03.018

Cited by 34 publications

(44 citation statements)

References 31 publications

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“…In numerical terms, this is described by decreases in NAP IC 50 s in the presence of 5-NU to levels approaching, or less than, the NAP IC 50 of worms in the absence of any additive (no PHB, no 5-NU) ( Table 1). The extent of the shift in IC 50 in the presence of synergist is described in Table 1, with synergism ratios at each PHB level. The addition of 5-NU to assays resulted in significant reductions in IC 50 at each PHB level, with synergism ratios up to 18.2-fold.…”

Section: Resultsmentioning

confidence: 99%

“…The extent of the shift in IC 50 in the presence of synergist is described in Table 1, with synergism ratios at each PHB level. The addition of 5-NU to assays resulted in significant reductions in IC 50 at each PHB level, with synergism ratios up to 18.2-fold. The dose response of worms in the presence of PHB and 5-NU was similar to that of the worms not exposed to PHB; that is, the 5-NU was able to completely reverse the PHB-induced drug tolerance.…”

Section: Resultsmentioning

confidence: 99%

“…UDPGT enzymes are also known to exist in nematodes, with the H. contortus genome possessing 34 UDPGT genes (26) and C. elegans known to possess 72 genes (47). While there are some reports of conjugation of glucose to benzimidazole anthelmintics in C. elegans (48) and H. contortus (49,50), there have, to our knowledge, been no reports of the conjugation of glucuronic acid, mediated by UDPGT enzymes, as a pathway of xenobiotic detoxification in parasitic worms prior to the present study.…”

Section: Discussionmentioning

confidence: 99%

“…3A and Table 1) could be increased if the worms were exposed to the synergist for a period prior to exposure to NAP. Table 3 shows that preexposure to 5-NU concentrations of 0.5 mM, 1 mM, and 2 mM resulted in significant decreases in the NAP IC 50 compared to values obtained with worms not exposed to 5-NU. ANOVA comparing IC 50 s from nonpretreated larvae (from Table 1) and pretreated larvae (from Table 3) in the absence of PHB showed that pretreatment significantly (P ϭ 0.05) increased the synergistic effects for 1 mM 5-NU (synergism ratio of 1.4 compared to 3.2); however, pretreatment had no effect at 2 mM 5-NU (ratio of 2.0 compared to 2.9).…”

Section: Fig 2 Effect Of Phenobarbital (Phb) On the Sensitivity Of Hmentioning

confidence: 93%

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Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

Kotze

Ruffell

Ingham

2014

Antimicrob Agents Chemother

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We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with Haemonchus contortus larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH) S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC 50 ) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that H. contortus larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Fig 2 Effect Of Phenobarbital (Phb) On the Sensitivity Of Hmentioning

confidence: 93%

See 2 more Smart Citations

Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

Kotze

Ruffell

Ingham

2014

Antimicrob Agents Chemother

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“…In this sense, some previous studies were addressed, particularly for BZ, to specify the enzymes involved, by identifying the metabolites formed by parasites. Under this approach, the ability of different helminth parasites to metabolize BZ was studied (Cvilink et al, 2008;Solana et al, 2001;Vokřál et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Development of novel valerolactam-benzimidazole hybrids anthelmintic derivatives: Diffusion and biotransformation studies in helminth parasites

Munguía

Michelena

Melian

et al. 2015

Experimental Parasitology

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Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine

Ajani

Aderohunmu

Ikpo

et al. 2016

Archiv der Pharmazie

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Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research. They are structural isosteres of naturally occurring nucleotides, which allows them to interact with the biopolymers of living systems. Hence, there is a need to couple the latest information with the earlier documentations to understand the current status of the benzimidazole nucleus in medicinal chemistry research. This present work unveils the benzimidazole core as a multifunctional nucleus that serves as a resourceful tool of information for synthetic modifications of old existing candidates in order to tackle drug resistance bottlenecks in therapeutic medicine. This manuscript deals with the recent advances in the synthesis of benzimidazole derivatives, the widespread biological activities as well as pharmacokinetic reports. These present them as a toolbox for fighting infectious diseases and also make them excellent candidates for future drug design.

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Biotransformation of albendazole and activities of selected detoxification enzymes in Haemonchus contortus strains susceptible and resistant to anthelmintics

Cited by 34 publications

References 31 publications

Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

Development of novel valerolactam-benzimidazole hybrids anthelmintic derivatives: Diffusion and biotransformation studies in helminth parasites

Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine

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