Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire, UK.
Pest Manag Sci. 2012 Jan;68(1):38-48. doi: 10.1002/ps.2218. Epub 2011 Jun 16.
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.
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.
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.
在整个生物体上进行杀虫剂发现筛选，是为了筛选出靶位处化学活性产生的效力。然而，许多潜在的杀虫化合物在体内自然解毒，无法到达靶位。据推测，其外来化合物解毒机制受损的昆虫品系可用于鉴定那些在筛选中通常无法显示的化合物；然后可以更合理地设计这些化合物以提高其生物利用度。该策略使用改变 Cyp6g1 和 Dhr96 表达的转基因果蝇系进行了测试。
观察到 Cyp6g1 敲低转基因系对测试化合物吡虫啉的敏感性增加，而 Dhr96 敲低转基因系具有抗性。通过使用增效醚处理和基因表达谱分析，发现了对外来化合物暴露的系统反应的证据。还观察到 DHR96 调控的性特异性基因表达。
这些结果证实了这种化学发现方法可以鉴定那些逃避传统筛选的化合物。该系统的复杂性意味着可能需要一组单一和多种基因敲低转基因系。
