一种基于不良结局途径研究暴露和药代动力学对高通量体外化学筛选影响的工作流程。
A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways.
作者信息
Phillips Martin B, Leonard Jeremy A, Grulke Christopher M, Chang Daniel T, Edwards Stephen W, Brooks Raina, Goldsmith Michael-Rock, El-Masri Hisham, Tan Yu-Mei
机构信息
Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA.
出版信息
Environ Health Perspect. 2016 Jan;124(1):53-60. doi: 10.1289/ehp.1409450. Epub 2015 May 15.
BACKGROUND
Adverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals.
OBJECTIVES
We developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition.
METHODS
Thirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood-brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites.
RESULTS
Application of the workflow screened 10 "low-priority" chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation.
CONCLUSIONS
The incorporation of exposure and ADME properties into the conceptual workflow eliminated 10 "low-priority" chemicals that may otherwise have undergone additional, resource-consuming analyses. Our workflow also increased confidence in interpretation of in vitro results by identifying possible "false negatives."
CITATION
Phillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. 2016. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways. Environ Health Perspect 124:53-60; http://dx.doi.org/10.1289/ehp.1409450.
背景
不良结局途径（AOPs）将个体或人群中的不良影响与分子起始事件（MIE）联系起来，而分子起始事件可以通过体外方法进行量化。AOPs在化学物质特异性风险评估中的实际应用需要纳入有关暴露的知识，以及化学物质的吸收、分布、代谢和排泄（ADME）特性。
目的
我们开发了一个概念性工作流程，以研究与分子起始事件相关的暴露和ADME特性。使用先前建立的AOP（乙酰胆碱酯酶（AChE）抑制）对该工作流程的实用性进行了评估。
方法
对在ToxCast™试验中发现可抑制人AChE的30种化学物质的暴露、吸收潜力和穿过血脑屏障（BBB）的能力进行了研究。将活性化学物质的结构与1029种非活性化学物质的结构进行比较，以检测可能具有活性代谢物的母体化合物。
结果
该工作流程的应用筛选出了30种活性化学物质中的10种“低优先级”化学物质。1029种非活性化学物质中有52种与其最接近的活性邻居的相似性阈值≥75%。在这52种化合物中，30种由于吸收或分布不佳而被排除。其余22种化合物可能直接或通过代谢活化在体内抑制AChE。
结论
将暴露和ADME特性纳入概念性工作流程，排除了10种“低优先级”化学物质，否则这些化学物质可能会进行额外的、消耗资源的分析。我们的工作流程还通过识别可能的“假阴性”结果，增强了对体外结果解释的信心。
引用文献
Phillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. 2016. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways. Environ Health Perspect 124:53-60; http://dx.doi.org/10.1289/ehp.1409450.
Zotero 插件