All drugs in development undergo toxicity testing in animals. Alternatives to animal experimentation for toxicity testing in drug development need to provide improved economics of toxicity screening or greater reliability in predicting human toxicity. Currently available alternatives do not meet these requirements particularly well. CXR Biosciences Ltd. proposes to generate transgenic cell lines that combine humanised drug metabolism characteristics with reporter gene systems that permit quick and convenient detection of early indicators of various toxic responses. Since metabolism by cytochrome P450s, particularly in the liver, is a major determinant of drug toxicity, the cell lines generated under this proposal will express the human cytochrome P450s primarily responsible for drug metabolism in the liver and up to four reporter genes chosen to allow simultaneous detection of toxic mechanisms such as oxidative stress, DNA damage, apoptosis or cell cycle arrest/hyperplasia. The project will include validation of the cell lines as predictors of human toxicity. Adoption of these cell lines by industry will allow reduction in animal numbers used in toxicological screening. The cell lines will permit rapid determination of mechanisms of drug toxicity relevant to the human and the project will establish the technical and conceptual framework for developing further transgenic cell lines as alternatives to animal experimentation in drug development.
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