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UGT Enzymes In Chemotherapeutic Drug Metabolism: New Avenues To Improve Drug Response And Overcome Resistance
Funder
National Health and Medical Research Council
Funding Amount
$610,005.00
Summary
Tumours treated by chemotherapy often become resistant to the drugs, leading to relapse and reduced chance of survival. We will study one of the main pathways leading to drug resistance, which could lead to the development of new ways to overcome resistance and improve cancer treatment outcomes.
Over-expression Of Human Cytochrome P450 2J2 Activates Phase II Biotransformation Genes That Influence Anti-cancer Drug Efficacy
Funder
National Health and Medical Research Council
Funding Amount
$489,155.00
Summary
Increased expression of some enzymes in human tumours contributes to anticancer drug resistance. In many tumours the fatty acid epoxygenase cytochrome P450 2J2 (CYP2J2) is over-expressed. We have found that CYP2J2 activates the expression of phase II enzymes that eliminate anticancer drugs; this is mediated by fatty acid epoxides. In this project we will define the underlying mechanisms of these effects, which may lead to novel strategies to overcome anticancer drug resistance.
A Novel Metabolic Role For UDP Glycosyltransferase 8 (UGT8)
Funder
National Health and Medical Research Council
Funding Amount
$419,144.00
Summary
The UDP glycosyltransferases (UGTs) are a family of enzymes that remove drugs and toxins from the human body as well as control levels of naturally produced molecules such as bile acids and hormones. We found that a new member of this family called UGT8 processes bile acids in the kidney and intestine and can affect how bile acids act to regulate metabolism. Our studies uncover new roles for bile acids in liver, kidney and gut health and in metabolic disorders such as diabetes and obesity.
Regulation Of Drug Detoxifying UDP Glucuronosyltransferases
Funder
National Health and Medical Research Council
Funding Amount
$590,945.00
Summary
Some organs in the body are particularly sensitive to fat-soluble chemicals taken in from the environment or present in food. They are also sensitive to hormones and other small molecule products of metabolism. Controlling the levels of these potentially toxic chemicals is essential in order to maintain the health of the organ. In this work we will investigate the regulation of detoxifying enzymes that protect these organs by inactivating and hastening the elimination of fat-soluble chemicals.
Characterization Of The Novel Drug And Xenobiotic Metabolizing UGT3A Enzyme Family
Funder
National Health and Medical Research Council
Funding Amount
$578,352.00
Summary
The elimination of chemicals made in the body or from environmental sources is essential for the maintenance of good health and the prevention of debilitating diseases. We have discovered two enzymes that use glucose and other sugars to detoxify fat-soluble chemicals. In this project we will study how these enzymes work and how they are regulated in the body. With this knowledge, we may be able to target the processes of drug and chemical detoxification to make them more efficient.
Molecular Determinants Of UDP Glucuronosyltransferase 1A3 And 1A4 Expression
Funder
National Health and Medical Research Council
Funding Amount
$516,078.00
Summary
Enzymes in the liver and gastrointestinal tract have a crucial role in protecting against the toxic effects of fat-soluble chemicals. Two of these enzymes called UGT1A3 and UGT1A4 have a special role in protecting against drugs and toxins that contain nitrogen groups. The levels of these two enzymes in the liver and gut vary extensively between individuals. In this project we will determine how the levels of these enzymes are controlled and what is the cause of this variability between individua ....Enzymes in the liver and gastrointestinal tract have a crucial role in protecting against the toxic effects of fat-soluble chemicals. Two of these enzymes called UGT1A3 and UGT1A4 have a special role in protecting against drugs and toxins that contain nitrogen groups. The levels of these two enzymes in the liver and gut vary extensively between individuals. In this project we will determine how the levels of these enzymes are controlled and what is the cause of this variability between individuals. This will help us predict those individuals who are more at risk from the adverse effects of nitrogen-containing drugs and from the toxic effects of chemicals in the diet or the environment. This project will also help us develop methods to increase the levels of these protective enzymes and help reduce the effects of exposure to toxic chemicals.Read moreRead less
UDP Glucuronosyltransferases As Regulators Of Signaling Pathways Modulated By Chemical Ligands.
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
Cells respond to their surroundings by transferring information received at the cell surface to the nucleus leading to changes in gene expression. There are many signaling pathways which transfer this informatrion to the nucleus. Some of these pathways are controlled by small molecules, usually fat-soluble chemicals. As a family of enzymes, the UDP glucuronosyltransferases (UGT) have evolved to eliminate fat-soluble chemicals, we propose that UGTs play a pivotal role in regulating the concentrat ....Cells respond to their surroundings by transferring information received at the cell surface to the nucleus leading to changes in gene expression. There are many signaling pathways which transfer this informatrion to the nucleus. Some of these pathways are controlled by small molecules, usually fat-soluble chemicals. As a family of enzymes, the UDP glucuronosyltransferases (UGT) have evolved to eliminate fat-soluble chemicals, we propose that UGTs play a pivotal role in regulating the concentrations of fat-soluble chemicals involved in signaling, and thus are important in controlling gene expression. We intend to provide evidence for this novel role of UGTs in this project. This information will be used to alter the response of the cell to its environment. For example, to help protect the cell against environmental toxins, or to make a cancer cell more susceptible to a chemotherapeutic agent.Read moreRead less
Probing UDP-glucuronosyltransferase Protein-protein Interactions: The Power Of Two.
Funder
National Health and Medical Research Council
Funding Amount
$482,710.00
Summary
Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransfera ....Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransferase (UGT) is one of the most important enzymes involved in drug and chemical metabolism. Consistent with its ability to metabolise such a large number of compounds, UGT is known to exist as a 'superfamily' of structurally related proteins. Despite the importance of UGT, little is known about the structural characteristics of these enzymes that are responsible for recognising and binding different classes of chemicals. Accumulating evidence from this and other laboratories indicates that the individual UGT proteins may combine with themselves (to form a homodimer) and with other UGT proteins (to form heterodimers). This project largely seeks to define the scope of UGT homo- and hetero- dimerisation, identify the structural elements of the proteins responsible for association and characterise the functional significance of dimerisation. The project will further explore associations between UGTs and other proteins, namely albumin. Characterisation of UGT dimerisation and associations with other proteins is fundamental to our understanding of how this enzyme functions and selects particular chemicals for metabolism. The work also has important implications for the devlopment and interpretation of in vitro (or 'test-tube') approaches for predicting how drugs are metabolised in humans. Such tests are widely employed in research and pharmaceutical company laboratories to predict how the body 'handles' new drugs prior to their administration to humans.Read moreRead less
Molecular Determinants Of UDP Glucuronosyltransferase Expression In The Gastrointestinal Tract
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
The gastrointestinal tract is a major portal of entry for dietary chemicals and drugs taken orally or as suppositories. Enzymes resident in the gastrointestinal tract have an essential role in preventing these chemicals from reaching other organs and target tissues in the body and in protecting the gastrointestinal tract per se from their effects. The levels of these enzymes in the gastrointestinal tract varies quite extensively between individuals. In this project we will determine how these en ....The gastrointestinal tract is a major portal of entry for dietary chemicals and drugs taken orally or as suppositories. Enzymes resident in the gastrointestinal tract have an essential role in preventing these chemicals from reaching other organs and target tissues in the body and in protecting the gastrointestinal tract per se from their effects. The levels of these enzymes in the gastrointestinal tract varies quite extensively between individuals. In this project we will determine how these enzymes are regulated and what causes the large differences in their levels between individuals. This will help us to predict those individuals who are more at risk from the adverse effects of drugs taken orally or as suppositories and from the toxic effects of chemicals in the diet. The project will also help us identify therapies that can increase the levels of these protective enzymes to help reduce the effects of exposure to toxic chemicals .Read moreRead less