Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, USA.
Annu Rev Anal Chem (Palo Alto Calif). 2012;5(1):79-105. doi: 10.1146/annurev.anchem.111808.073659. Epub 2012 Apr 5.
New chemicals or drugs must be guaranteed safe before they can be marketed. Despite widespread use of bioassay panels for toxicity prediction, products that are toxic to a subset of the population often are not identified until clinical trials. This article reviews new array methodologies based on enzyme/DNA films that form and identify DNA-reactive metabolites that are indicators of potentially genotoxic species. This molecularly based methodology is designed in a rapid screening array that utilizes electrochemiluminescence (ECL) to detect metabolite-DNA reactions, as well as biocolloid reactors that provide the DNA adducts and metabolites for liquid chromatography-mass spectrometry (LC-MS) analysis. ECL arrays provide rapid toxicity screening, and the biocolloid reactor LC-MS approach provides a valuable follow-up on structure, identification, and formation rates of DNA adducts for toxicity hits from the ECL array screening. Specific examples using this strategy are discussed. Integration of high-throughput versions of these toxicity-screening methods with existing drug toxicity bioassays should allow for better human toxicity prediction as well as more informed decision making regarding new chemical and drug candidates.
新的化学物质或药物在上市之前必须保证安全。尽管生物测定小组被广泛用于毒性预测，但直到临床试验才发现对人群中的一部分有毒的产品。本文综述了基于酶/DNA 薄膜的新的阵列方法，这些方法形成并识别出 DNA 反应性代谢物，这些代谢物是潜在遗传毒性物质的指标。这种基于分子的方法设计成快速筛选阵列，利用电致化学发光（ECL）来检测代谢物-DNA 反应，以及生物胶体反应器，为液相色谱-质谱（LC-MS）分析提供 DNA 加合物和代谢物。ECL 阵列提供快速毒性筛选，而生物胶体反应器 LC-MS 方法为 ECL 阵列筛选中的毒性命中物提供了 DNA 加合物的结构、鉴定和形成速率的有价值的后续分析。讨论了使用这种策略的具体例子。将这些毒性筛选方法的高通量版本与现有的药物毒性生物测定方法相结合，应该可以更好地预测人类毒性，并在新的化学物质和药物候选物方面做出更明智的决策。
