Insecticide detoxification indicator strains as tools for enhancing chemical discovery screens
Insecticide detoxification indicator strains as tools for enhancing chemical discovery screens
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DOI：
10.1002/ps.2218
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发表时间：
2012-01-01
影响因子：
4.1
通讯作者：
Hadfield, Stephen
中科院分区：
文献类型：
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作者：
Shah, Sheetal;Yarrow, Carol;Hadfield, Stephen
背景：在整个生物体上进行的胰岛素发现筛选是为了筛选靶位点化学活性产生的效价。然而，许多潜在的杀虫化合物在体内天然解毒，不能到达靶位点。据推测，昆虫品系与其异生物质解毒机制受损，可用于识别这些化合物，通常无法显示在屏幕上，这些化合物可以更合理地设计，以提高其生物利用度。结果：Cyp6g1基因敲除的转基因果蝇对供试化合物吡虫啉的敏感性增加，而Dhr96基因敲除的转基因果蝇对供试化合物吡虫啉的抗性增加。通过胡椒基丁醚治疗和基因表达谱分析，发现了对外源性暴露的全身反应的证据。性别特异性基因表达调控的DHR96也observed.CONCLUSION：结果证实，这种方法来化学发现可以识别化合物逃脱传统的屏幕。该系统的复杂性意味着可能需要一组单基因和多基因敲低转基因系。(C)2011年化学工业协会
BACKGROUND: Insecticide discovery screens carried out on whole organisms screen for potency resulting from chemical activity at the target site. However, many potentially insecticidal compounds are naturally detoxified in vivo and do not make it to the target site. It is hypothesised that insect strains with their xenobiotic detoxification machinery compromised could be used to identify such compounds that normally fail to show up in screens; these compounds could then be more rationally designed to increase their bioavailability. This strategy was tested with transgenic Drosophila lines with altered expression of Cyp6g1 and Dhr96.RESULTS: It was observed that Cyp6g1 knockdown transgenic lines have increased susceptibility to the test compound imidacloprid, while Dhr96 knockdown transgenic lines are resistant. Evidence was found for a systemic response to xenobiotic exposure, uncovered by piperonyl butoxide treatment and by gene expression profiling. Sex-specific gene expression regulated by DHR96 was also observed.CONCLUSION: The results confirm that this approach to chemical discovery could identify compounds that escape traditional screens. The complexity of the system means that a panel of single and multiple gene knockdown transgenic lines may be required. (C) 2011 Society of Chemical Industry