NHR-176 regulates <i>cyp-35d1</i> to control hydroxylation-dependent metabolism of thiabendazole in <i>Caenorhabditis elegans</i>

Jones, Laura M.; Flemming, Anthony J.; Urwin, Peter E.

doi:10.1042/bj20141296

Cited by 30 publications

(23 citation statements)

References 67 publications

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“…The CYPs show increased expression when exposed to xenobiotic [115,116]. In C. elegans, the overexpression of cyps35 has been reported against albendazole [115] and TBZ [116] exposure, while TBZ was metabolized by CYP35D1 [118]. The gene HCON_00143950 is an orthologue of C. elegans CYP33.…”

Section: Discussionmentioning

confidence: 99%

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

Khan

Nisar

Yuan

et al. 2020

Genes

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The most important and broad-spectrum drug used to control the parasitic worms to date is ivermectin (IVM). Resistance against IVM has emerged in parasites, and preserving its efficacy is now becoming a serious issue. The parasitic nematode Haemonchus contortus (Rudolphi, 1803) is economically an important parasite of small ruminants across the globe, which has a successful track record in IVM resistance. There are growing evidences regarding the multigenic nature of IVM resistance, and although some genes have been proposed as candidates of IVM resistance using lower magnification of genome, the genetic basis of IVM resistance still remains poorly resolved. Using the full magnification of genome, we herein applied a population genomics approach to characterize genome-wide signatures of selection among pooled worms from two susceptible and six ivermectin-resistant isolates of H. contortus, and revealed candidate genes under selection in relation to IVM resistance. These candidates also included a previously known IVM-resistance-associated candidate gene HCON_00148840, glc-3. Finally, an RNA-interference-based functional validation assay revealed the HCON_00143950 as IVM-tolerance-associated gene in H. contortus. The possible role of this gene in IVM resistance could be detoxification of xenobiotic in phase I of xenobiotic metabolism. The results of this study further enhance our understanding on the IVM resistance and continue to provide further evidence in favor of multigenic nature of IVM resistance.

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Section: Discussionmentioning

confidence: 99%

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

Khan

Nisar

Yuan

et al. 2020

Genes

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“…Finally, BZ resistance in ascarids might be associated with non-drug target related resistance mechanisms. In C. elegans as well as in strongylid parasites, BZs can be metabolised by cytochrome P450 monooxygenases and also induce expression of P-glycoproteins (Kerboeuf et al., 2003, Laing et al., 2010, Jones et al., 2013, Jones et al., 2015). Inhibitors of P-glycoproteins and cytochrome P450 monooxygenases potentiate the effects of BZs in C. oncophora and O. ostertagi in in vitro assays (AlGusbi et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

Reduced efficacy of albendazole against Ascaris lumbricoides in Rwandan schoolchildren

Krücken

Fraundorfer

Mugisha

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

120

112

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Control of human soil-transmitted helminths (STHs) relies on preventive chemotherapy of schoolchildren applying the benzimidazoles (BZ) albendazole or mebendazole. Anthelmintic resistance (AR) is a common problem in nematodes of veterinary importance but for human STHs, information on drug efficacy is limited and routine monitoring is rarely implemented. Herein, the efficacy of single dose albendazole (400 mg) was evaluated in 12 schools in the Huye district of Rwanda where Ascaris is the predominant STH. Ascaris eggs were detected by wet mount microscopy and the Mini-FLOTAC method to assess cure rate (CR) and faecal egg count reduction (FECR). Blood and faecal samples were analysed for co-infections with Plasmodium sp. and Giardia duodenalis, respectively. Ascaris positive samples collected before and after treatment were analysed for putatively BZ-resistance associated β-tubulin gene single nucleotide polymorphisms. The overall CR was 69.9% by Mini-FLOTAC and 88.6% by wet mount microscopy. The FECR was 75.4% and the 95% calculated confidence intervals were 50.4–87.8% using sample variance, 55.4–88.8% by bootstrapping, and 75.0–75.7% applying a Markov Chain Monte Carlo Bayesian approach. FECR varied widely between 0 and 96.8% for individual schools. No putative BZ-resistance associated polymorphisms were found in the four Ascaris β-tubulin isotype genes examined. Since FECRs <95% indicate reduced efficacy, these findings raise the suspicion of BZ resistance. In the absence of respective molecular evidence, heritable AR in the local Ascaris populations cannot be formally proven. However, since FECRs <95% indicate reduced efficacy, BZ resistance may be suspected which would be alarming and calls for further analyses and routine monitoring in preventive chemotherapy programs.

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“…Xenobiotics are known to induce the expression of metabolic enzymes 31 32 . Therefore the differential metabolism we observed among analogues might result either from their intrinsic susceptibility to metabolism or from their ability to induce metabolic gene expression.…”

Section: Resultsmentioning

confidence: 99%

The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome

Harlow

Perry

Widdison³

et al. 2016

Sci Rep

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To determine whether a C. elegans bioassay could predict mammalian developmental activity, we selected diverse compounds known and known not to elicit such activity and measured their effect on C. elegans egg viability. 89% of compounds that reduced C. elegans egg viability also had mammalian developmental activity. Conversely only 25% of compounds found not to reduce egg viability in C. elegans were also inactive in mammals. We conclude that the C. elegans egg viability assay is an accurate positive predictor, but an inaccurate negative predictor, of mammalian developmental activity. We then evaluated C. elegans as a tool to identify mechanisms affecting toxicological outcomes among related compounds. The difference in developmental activity of structurally related fungicides in C. elegans correlated with their rate of metabolism. Knockdown of the cytochrome P450s cyp-35A3 and cyp-35A4 increased the toxicity to C. elegans of the least developmentally active compounds to the level of the most developmentally active. This indicated that these P450s were involved in the greater rate of metabolism of the less toxic of these compounds. We conclude that C. elegans based approaches can predict mammalian developmental activity and can yield plausible hypotheses for factors affecting the biological potency of compounds in mammals.

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NHR-176 regulates cyp-35d1 to control hydroxylation-dependent metabolism of thiabendazole in Caenorhabditis elegans

Cited by 30 publications

References 67 publications

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

Reduced efficacy of albendazole against Ascaris lumbricoides in Rwandan schoolchildren

The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome

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