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

遗传毒性的新机制：UDP-葡萄糖醛酸基转移酶对羧酸药物的生物活化

• 批准号: nhmrc : 250320
• 负责人: A/Pr Benedetta Sallustio
• 金额: $ 13.65万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/novel-mechanisms-genotoxicity-udp-glucuronosyltransferases/77816
• 关键词: Novel; mechanisms; genotoxicity; bioactivation; carboxylic

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.

在任何新的药品被批准用于临床使用之前，它们都要经过广泛的测试，以证明其有效性和安全性。这种测试的一部分包括确保它们在体内不会转化为能够破坏DNA的化学反应形式，因为DNA损伤会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，身体将药物转化为一种叫做葡萄糖醛酸酯的反应性化学物质。我们已经证明了一些酯类葡萄糖醛酸能破坏DNA。许多不同的药物都有可能形成葡萄糖醛酸酯。然而，我们不知道是否所有的酯类葡萄糖醛酸酯都会导致DNA损伤，或者，如果只有一些会，是什么特性决定了它们的DNA损伤潜力。此外，目前大多数临床前筛选的药物无法检测到酯类葡糖苷引起的DNA损伤。我们认为，这种知识的缺乏令人严重关切。因此，本项目的目标是：i)筛选大量酯葡糖苷介导的DNA损伤药物；ii)发展一些初步的方法来预测这些反应性化学物质的DNA损伤效力；iii)开发一种筛选试验，该试验可能更适合于在临床前试验中检测葡萄糖醛酸酯引起的DNA损伤。这种工作对于确保所有药物制剂的持续安全至关重要。