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Toxicity screening using biosensors that measure DNA damage
James F Rusling1, Eli G Hvastkovs, John B Schenkman
1Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, USA. james.rusling@uconn.edu
Abstract:
Toxicity continues to be a major cause of drug development failures. An assessment of drug toxicity as early in the discovery/development cycle as possible is important to minimize the economic impact of discontinuing a drug late in development. Currently, batteries of biological testing protocols provide good assessment and predictions of toxicity in the general population; however, new cost-effective procedures based on simpler biochemical systems that are arranged in biosensor formats are emerging that may be very useful for early toxicity screening. In particular, biosensors employing thin films of DNA and pure metabolic enzymes show promise in predicting genotoxicity. In such biosensor systems, the enzyme/drug reaction is run in a DNA/enzyme film, which acts as a nanoreactor to produce metabolites in close proximity to high concentrations of DNA. The rate of damage to the DNA is then taken as the genotoxicity endpoint. Formation of nucleobase-drug adducts is detected by catalytic voltammetry capillary LC-MS after hydrolysis of the DNA, or optically by incorporating an electrochemiluminescent polymer into the biosensor films. Similar sensors using a redox polymer specific for 8-oxoguanine in DNA can be used to monitor oxidative stress. The most advanced genotoxicity biosensors feature arrays that can contain many metabolic enzymes, such as cytochrome P450s. Arrays based on electrochemiluminescence can be read using a simple apparatus featuring a charge-coupled device camera. These arrays can obtain relative genotoxicity data for a series of enzymes simultaneously. This new biosensor technology is compared to other emerging methods for toxicity screening.
Insights
New biosensors using DNA and enzymes offer a cost-effective method for early drug toxicity screening, specifically predicting genotoxicity by measuring DNA damage. This approach aids in minimizing late-stage drug development failures.
Area of Science:
- Biochemistry
- Nanotechnology
- Drug Development
Background:
- Drug development failures are often caused by toxicity, necessitating early assessment.
- Current toxicity testing is effective but costly; emerging biosensor technologies offer potential cost-effective alternatives.
- Early toxicity screening is crucial to reduce economic losses from late-stage drug discontinuation.
Purpose of the Study:
- To introduce and evaluate novel biosensor systems for early toxicity screening, focusing on genotoxicity prediction.
- To highlight the advantages of biosensors employing DNA and metabolic enzymes for cost-effective drug safety assessment.
- To compare these advanced biosensor technologies with other emerging toxicity screening methods.
Main Methods:
- Development of biosensors utilizing thin films of DNA and metabolic enzymes (e.g., cytochrome P450s) as nanoreactors.
- Detection of DNA damage via nucleobase-drug adduct formation using catalytic voltammetry capillary LC-MS or optical methods (electrochemiluminescence).
- Monitoring oxidative stress using redox polymers specific for 8-oxoguanine; advanced arrays enable simultaneous multi-enzyme analysis.
Main Results:
- Biosensors effectively measure DNA damage rates as a genotoxicity endpoint.
- Optical and electrochemical detection methods provide sensitive assessment of drug-induced DNA damage.
- Enzyme-based biosensor arrays allow for simultaneous relative genotoxicity assessment across multiple metabolic pathways.
Conclusions:
- Biosensors integrating DNA and metabolic enzymes represent a promising, cost-effective approach for early genotoxicity screening.
- This technology can significantly aid in identifying potential drug toxicity early in the development pipeline.
- Advanced biosensor arrays offer efficient, simultaneous analysis, improving the speed and scope of toxicity assessments.
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