Previously, we observed that the transcription levels of 8 cytochrome P450 monooxygenase (P450) and 10 ATP binding cassette (ABC) transporter genes were increased in human body lice, Pediculus humanus humanus, following the non-invasive induction assay (NIIA) using a sublethal amount of ivermectin. To identify a similar mechanism in a model insect, Drosophila melanogaster, we selected six orthologous genes (Cyp9f2, Cyp6g2, Cyp9h1, MRP1, GC1824 as an ABCB type, and CG3327 as an ABCG type) corresponding to the three P450 and three ABC transporter genes, respectively, that were highly induced in P. humanus. When the NIIA was conducted with 90 ppm ivermectin (LC3 at 24 hours) by topical application, transcription levels of Cyp9f2 and MRP1 were up-regulated at 3 h post-treatment and those of Cyp6g2, Cyp9h1, MRP1, GC1824 and CG3327 were increased at 6 h post-treatment in D. melanogaster. Contact bioassays using UAS-RNAi transgenic lines of D. melanogaster, each of which targeted the knockdown of an induced gene, was conducted to determine the association of these major genes with ivermectin resistance. Increased susceptibility to ivermectin was observed in the Cyp9f2, Cyp6g2, Cyp9h1 or MRP1-knockdown flies. Considering that these four genes are orthologous to CYP9AG2, CYP6CJ1, CYP9AG1 and ABCC4, which were the most highly over-expressed following NIIA with ivermectin in P. humanus, the current results suggest that these genes are also associated with ivermectin detoxification in D. melanogaster and that both P. humanus and D. melanogaster are likely to share, in part, similar mechanisms of tolerance to ivermectin.

RNAi validation of detoxification genes involved in ivermectin tolerance in Drosophila melanogaster

254th National Meeting (2017)

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