Journal
ANNUAL REVIEW OF ANALYTICAL CHEMISTRY, VOL 5
Volume 5, Issue -, Pages 79-105Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev.anchem.111808.073659
Keywords
toxicity; genotoxicity; DNA damage; cytochrome P450; screening; high throughput; drugs; metabolism
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Funding
- NIEHS NIH HHS [R01 ES003154, ES03154] Funding Source: Medline
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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.
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