Novel Mechanisms Of Genotoxicity: Bioactivation Of Carboxylic Acid Drugs By UDP-glucuronosyltransferases
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
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 sho ....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.Read moreRead less
DAMAGE TO SPECIFIC MITOCHONDRIAL MEMBRANE PROTEINS DURING OXIDATIVE STRESS AND THE AGEING PROCESS
Funder
National Health and Medical Research Council
Funding Amount
$195,982.00
Summary
During the ageing process and exposure to certain drugs or chemicals, oxygen radicals are produced within cells and tissues. If unchecked, these cause damage to a number of cell components, resulting in tissue death. One target for oxygen radicals are proteins in mitochondria, the powerhouses of the cell that are responsible for meeting cell energy needs. It is well known that the ability of mitochondria to maintain energy supplies decreases in old age. Over the past decade, research has shown t ....During the ageing process and exposure to certain drugs or chemicals, oxygen radicals are produced within cells and tissues. If unchecked, these cause damage to a number of cell components, resulting in tissue death. One target for oxygen radicals are proteins in mitochondria, the powerhouses of the cell that are responsible for meeting cell energy needs. It is well known that the ability of mitochondria to maintain energy supplies decreases in old age. Over the past decade, research has shown that this is partly due to mutation of genes in the DNA which is found in mitochondria. However it is also very likely that the loss of function in mitochondria during the ageing process is also due to the accumulation of protein damage. Recent work in insects has shown that specific proteins in mitochondria are extensively damaged during the ageing process and-or exposure to oxygen radicals. In higher organisms such as mice, however, exactly which mitochondrial proteins are targeted by oxygen radicals is unknown. This work will investigate the likelihood that proteins located in membranes of mitochondria are targets for damage by oxygen radicals and during the ageing process. Furthermore, since oxygen radicals readily attack polyunsaturated fatty acids in cell membranes, we are investigating the likelihood that toxic substances (unsaturated aldehydes) formed during membrane damage contribute to the damage to mitochondrial proteins during the ageing process.Read moreRead less
Mechanisms Of Epithelial Damage By The Noxious Smoke Constituent Acrolein
Funder
National Health and Medical Research Council
Funding Amount
$668,813.00
Summary
Due to increasing use of reactive chemicals by terrorists (e.g. chlorine gas), their effects on the lung are receiving increasing attention in the global toxicology community. This project focusses on acrolein, the major cytotoxic substance present in smoke produced on combustion of organic matter. We will explore the mechanisms whereby acrolein and high doses of smoke cause the lung to lose its watertight properties, and also test ways of preventing such damage with drugs.