Novel mechanisms of genotoxicity: bioactivation of carboxylic acid drugs by UDP-glucuronosyltransferases

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Before any new pharmaceutical products are approved for clinical use, they undergo extensive testing to demonstrate both efficacy and safety. Part of this testing involves ensuring that, within the body, they are not converted to chemically reactive forms able to damage DNA, since DNA damage can lead to cell toxicity or the development of cancer. Our laboratories have recently identified a new mechanism by which the body converts drugs to reactive chemicals called ester glucuronides. We have shown that some ester glucuronides can damage DNA. A large number of different drugs have the potential to form ester glucuronides. However, we do not know whether all ester glucuronides cause DNA damage or, if only some do, what properties determine their DNA damaging potential. In addition, most of the current pre-clinical screening of drugs can not detect DNA damage caused by ester glucuronides. We believe this lack of knowledge is of serious concern. Therefore, this project aims to: i) screen a large number of drugs for ester glucuronide-mediated DNA damage; ii) develop some preliminary methods of predicting the DNA damaging potency of these reactive chemicals; and iii) develop a screening test that may be more suitable for detecting DNA damage by ester glucuronides during pre-clinical testing. Such work is essential to ensure the ongoing safety of all pharmaceutical agents.