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

在任何新的医药产品被批准用于临床之前，它们都要经过广泛的测试，以证明其有效性和安全性。这项测试的一部分涉及确保它们在体内不会转化为能够损害DNA的化学活性形式，因为DNA损害可能导致细胞毒性或癌症的发展。我们的实验室最近发现了一种新的机制，通过这种机制，人体可以将药物转化为名为酯葡萄糖醛酸脂的活性化学物质。我们已经证明了一些酯葡萄糖醛酸苷可以损伤DNA。大量不同的药物有可能形成酯类葡萄糖醛酸苷。然而，我们不知道是否所有的酯葡糖醛酸化物都会引起DNA损伤，或者如果只有一些会造成DNA损伤，那么是什么性质决定了它们的DNA损伤潜力。此外，目前大多数临床前筛选的药物都无法检测到酯葡糖醛酸苷造成的DNA损伤。我们认为，这种缺乏知识的情况令人严重关切。因此，本项目的目标是：i)筛选大量的酯葡萄糖醛酸脂介导的DNA损伤的药物；ii)开发一些初步的方法来预测这些活性物质的DNA损伤效力；iii)开发一种更适合于在临床前测试中检测酯葡萄糖醛酸苷造成的DNA损伤的筛选试验。这项工作对于确保所有药剂的持续安全至关重要。

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.