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Published on: October 28, 2013
Metabolic toxicity screening using electrochemiluminescence arrays coupled with enzyme-DNA biocolloid reactors and
Eli G Hvastkovs1, John B Schenkman, James F Rusling
1Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, USA. hvastkovse@ecu.edu
Abstract:
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.
Insights
New enzyme/DNA film arrays rapidly screen for toxic metabolites using electrochemiluminescence (ECL). This method identifies genotoxic species, improving drug safety before clinical trials.
Area of Science:
- Biochemistry
- Toxicology
- Analytical Chemistry
Background:
- Current toxicity prediction methods often fail to identify population-specific toxic effects until late-stage clinical trials.
- Genotoxic species, which damage DNA, pose a significant risk and require robust detection methods.
- Early identification of potentially harmful chemicals and drugs is crucial for public health and regulatory approval.
Purpose of the Study:
- To review novel array methodologies for detecting DNA-reactive metabolites, which are indicators of genotoxic compounds.
- To present a rapid screening array utilizing electrochemiluminescence (ECL) for detecting metabolite-DNA reactions.
- To highlight the use of biocolloid reactors coupled with liquid chromatography-mass spectrometry (LC-MS) for detailed analysis of DNA adducts.
Main Methods:
- Development of enzyme/DNA film arrays for genotoxicity screening.
- Utilization of electrochemiluminescence (ECL) for rapid detection of metabolite-DNA interactions.
- Integration of biocolloid reactors with LC-MS for structural identification and quantification of DNA adducts.
Main Results:
- ECL arrays demonstrate rapid toxicity screening capabilities for potential genotoxic agents.
- The biocolloid reactor LC-MS approach successfully identifies and characterizes DNA adducts from screened compounds.
- This integrated strategy provides a comprehensive approach to toxicity assessment, from initial screening to detailed analysis.
Conclusions:
- Novel array methodologies based on enzyme/DNA films offer a promising approach for early toxicity prediction.
- Combining ECL screening with biocolloid reactor LC-MS analysis enhances the identification of genotoxic species.
- Integrating these high-throughput methods with existing bioassays can significantly improve human toxicity prediction and decision-making for new chemical and drug candidates.
