Detoxification of ivermectin by ATP binding cassette transporter C4 and cytochrome P450 monooxygenase 6CJ1 in the human body louse,<i>Pediculus humanus humanus</i>

Kim, J. H.; Gellatly, Kyle; Lueke, Bettina; Kohler, Maxie; Nauen, Ralf; Murenzi, Edwin; Yoon, Kyong Sup; Clark, J. Marshall

doi:10.1111/imb.12348

Cited by 25 publications

(21 citation statements)

References 42 publications

(56 reference statements)

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“…and Table ). Putative roles of these genes in phases I and III xenobiotic metabolism/detoxification reactions for ivermectin have been presented in our previous paper (Kim et al, ). The similar overexpression patterns in both body lice and D. melanogaster suggest that a similar ivermectin‐mediated induction mechanism may be present in these two species.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that xenobiotic‐detoxifying enzymes and transporters are, respectively, involved in the detoxification and efflux of insecticides and have been found to commonly cause resistance (Dermauw & Van Leeuwen, ; Liu et al, ). The metabolism of ivermectin is well studied in both invertebrates (Pohl et al, ; Riga et al, ; Kim et al, ) and vertebrates (Chiu et al, ; Lespine et al, ; Canga et al, ) and consistently results in three oxidative metabolites (24‐OH, 26‐OH and 3‐ O ‐desmethyl ivermectin) and the direct efflux of ivermectin by adenosine triphosphate binding cassette (ABC) transporters. Cytochrome P450 monooxygenases (P450s) are known to oxidatively detoxify various xenobiotics by phase I metabolic reactions, and ivermectin has been shown to be metabolized by CYP3A4 in humans (Zeng et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…The induction of tolerance by a short exposure to sublethal amount of ivermectin resulted in a significantly slower mortality response in vivo , and transcript profiling following exposure to ivermectin revealed elevated transcription of several P450 and ABC transporter genes. Among the genes identified, two of the most highly induced genes, PhABCC4 and CYP6CJ1 , were functionally expressed, and it was confirmed that ivermectin was effluxed directly by PhABCC4 and oxidatively metabolized by CYP6CJ1 under in vitro conditions (Kim et al, ).…”

Section: Introductionmentioning

confidence: 99%

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RNA interference validation of detoxification genes involved in ivermectin tolerance in Drosophila melanogaster

Kim

Moreau

Ali

et al. 2018

Insect Molecular Biology

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Previously, we observed increased transcription levels of specific cytochrome P450 monooxygenase (P450) and adenosine triphosphate binding cassette (ABC) transporter genes in human body lice, Pediculus humanus humanus, following exposure to ivermectin using the non-invasive induction assay, which resulted in tolerance. To confirm the roles of these genes in induction and tolerance, the robust genetic model insect Drosophila melanogaster was chosen. Orthologous genes corresponding to the body louse P450 (Cyp9f2, Cyp6g2 and Cyp9h1) and ABC transporter (Mrp1, GC1824 as an ABCB type and CG3327 as an ABCG type) genes were selected for in vivo bioassay. Following a brief treatment with a sublethal dose of ivermectin, the mortality response was significantly slower, indicating the presence of tolerance. Concurrently, the transcription levels of Cyp9f2 and Mrp1 at 3 h and those of Cyp6g2, Cyp9h1, Mrp1, CG1824 and CG3327 at 6 h post-treatment were upregulated, indicating gene induction. In behavioural bioassay using GAL4/UAS-RNA interference transgenic fly lines, increased susceptibility to ivermectin was observed following heat shock in the Cyp9f2 , Cyp6g2 , Cyp9h1 , Mrp1 or CG3327-knockdown flies. Considering that these five genes are orthologous to those which had the largest over-expression level following ivermectin-induced tolerance in the body louse, the current results suggest that they are also associated with ivermectin detoxification in D. melanogaster and that body lice and D. melanogaster are likely to share, in part, similar mechanisms of tolerance to ivermectin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RNA interference validation of detoxification genes involved in ivermectin tolerance in Drosophila melanogaster

Kim

Moreau

Ali

et al. 2018

Insect Molecular Biology

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“…However, whether the high expression of ABC transporter after insecticide induction is related to the detoxification metabolism of insects needs to be confirmed by further studies. PhABCC4 of Pediculus humanus humanus expressed in Xenopus oocytes functioned in ivermectin efflux, suggesting that Ph ABCC4 might be involved in ivermectin transport [112].…”

Section: Abc Transporters In Xenobiotic Detoxification By Insectsmentioning

confidence: 99%

Insect ATP-Binding Cassette (ABC) Transporters: Roles in Xenobiotic Detoxification and Bt Insecticidal Activity

Chakrabarty

Jin

et al. 2019

IJMS

117

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ATP-binding cassette (ABC) transporters, a large class of transmembrane proteins, are widely found in organisms and play an important role in the transport of xenobiotics. Insect ABC transporters are involved in insecticide detoxification and Bacillus thuringiensis (Bt) toxin perforation. The complete ABC transporter is composed of two hydrophobic transmembrane domains (TMDs) and two nucleotide binding domains (NBDs). Conformational changes that are needed for their action are mediated by ATP hydrolysis. According to the similarity among their sequences and organization of conserved ATP-binding cassette domains, insect ABC transporters have been divided into eight subfamilies (ABCA–ABCH). This review describes the functions and mechanisms of ABC transporters in insecticide detoxification, plant toxic secondary metabolites transport and insecticidal activity of Bt toxin. With improved understanding of the role and mechanisms of ABC transporter in resistance to insecticides and Bt toxins, we can identify valuable target sites for developing new strategies to control pests and manage resistance and achieve green pest control.

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“…80 In addition, ivermectin tolerance mediated by transcription of P450s and xenobiotic pumps can be induced in ticks, head lice, and Drosophila melanogaster. [81][82][83] Overall, this suggests that differential mechanisms of ivermectin tolerance and resistance occur and that cross-resistance is also possible via at least one of these mechanisms.…”

mentioning

confidence: 93%

A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool

Billingsley

Binka

Chaccour

et al. 2020

The American Journal of Tropical Medicine and Hygiene

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In the context of stalling progress against malaria, resistance of mosquitoes to insecticides, and residual transmission, mass drug administration (MDA) of ivermectin, an endectocide used for neglected tropical diseases (NTDs), has emerged as a promising complementary vector control method. Ivermectin reduces the life span of Anopheles mosquitoes that feed on treated humans and/or livestock, potentially decreasing malaria parasite transmission when administered at the community level. Following the publication by WHO of the preferred product characteristics for endectocides as vector control tools, this roadmap provides a comprehensive view of processes needed to make ivermectin available as a vector control tool by 2024 with a completely novel mechanism of action. The roadmap covers various aspects, which include 1) the definition of optimal dosage/regimens for ivermectin MDA in both humans and livestock, 2) the risk of resistance to the drug and environmental impact, 3) ethical issues, 4) political and community engagement, 5) translation of evidence into policy, and 6) operational aspects of large-scale deployment of the drug, all in the context of a drug given as a prevention tool acting at the community level. The roadmap reflects the insights of a multidisciplinary group of global health experts who worked together to elucidate the path to inclusion of ivermectin in the toolbox against malaria, to address residual transmission, counteract insecticide resistance, and contribute to the end of this deadly disease.

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Detoxification of ivermectin by ATP binding cassette transporter C4 and cytochrome P450 monooxygenase 6CJ1 in the human body louse,Pediculus humanus humanus

Cited by 25 publications

References 42 publications

RNA interference validation of detoxification genes involved in ivermectin tolerance in Drosophila melanogaster

RNA interference validation of detoxification genes involved in ivermectin tolerance in Drosophila melanogaster

Insect ATP-Binding Cassette (ABC) Transporters: Roles in Xenobiotic Detoxification and Bt Insecticidal Activity

A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool

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