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Glutathione Transferase Deficient Mice To Probe For Adverse Drug Reactions
Funder
National Health and Medical Research Council
Funding Amount
$562,933.00
Summary
A family of enzymes called glutathione transferases (GST) that metabolize foreign chemicals and therapeutic drugs have been shown to be a significant cause of drug resistance in cancer chemotherapy. It has been suggested that inhibitors of GSTs could be used in cancer treatment to counter drug resistance or to slow the metabolism and enhance the activity of some drugs. Some GSTs carryout important enzymatic reactions with endogenous substrates and others have important non-enzymatic functions su ....A family of enzymes called glutathione transferases (GST) that metabolize foreign chemicals and therapeutic drugs have been shown to be a significant cause of drug resistance in cancer chemotherapy. It has been suggested that inhibitors of GSTs could be used in cancer treatment to counter drug resistance or to slow the metabolism and enhance the activity of some drugs. Some GSTs carryout important enzymatic reactions with endogenous substrates and others have important non-enzymatic functions such as the regulation of signaling pathways within cells and the modulation of calcium ion channels that are involved in muscle contractions. The generic inhibition of all GSTs could therefore have significant adverse physiological effects. We propose to make mice deficient in specific GSTs and to study their physiological responses. The results of these studies will indicate which GSTs can be safely inhibited without the risk of deleterious side effects. These studies are important because adverse reactions to therapeutic drugs are a significant cause of hospital admissions and death.Read moreRead less
Pharmacogenetic Investigations Of Glutathione Transferases
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. This study will investigate (1)the genetic mechanisms that alter the production of glutathione transferases, (2) the character ....Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. This study will investigate (1)the genetic mechanisms that alter the production of glutathione transferases, (2) the characteristics of a new class of glutathione transferases and (3) the role of glutathione transferase A4 in protecting against disorders such as atherosclerosis and Parkinson's disease.Read moreRead less
Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cel ....Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cells can affect how much calcium flows through these calcium channels. The proteins were thought to have other functions and our discovery of their effect on ryanodine receptor calcium channels has caused considerable excitement. We now plan to explore how they do this. We will mutate specific regions of the proteins to discover which regions are important and which are not. We will also look at whether closely related proteins have similar effects. The new class of ion channel modulator that we are studying has the capacity to alter not only respiration, movement and cardiac contraction, but also other aspects cardiovascular function, neuronal activity and immune responses. Understanding the way in which soluble proteins can interact with ion channels may reveal a novel target for drugs that affect ryanodine receptor calcium channel function and allow the rational design of specific drugs to regulate ion channels or ion channel modulators.Read moreRead less
The Role Of Zeta And Omega Class Glutathione Transferases In Endobitic And Xenobiotc Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$481,980.00
Summary
The glutathione transferases are enzymes that play a significant role in the protection of cells from harmful chemicals in the environment. While some of the chemicals that are detoxified by glutathione transferases cause cancer, and other diseases, these enzymes also eliminate some of the drugs that are used in chemotherapy. Variations in the type and amount of glutathione transferase in a cell can make a normal cell susceptible to cancer causing chemicals and make a cancer cell resistant to an ....The glutathione transferases are enzymes that play a significant role in the protection of cells from harmful chemicals in the environment. While some of the chemicals that are detoxified by glutathione transferases cause cancer, and other diseases, these enzymes also eliminate some of the drugs that are used in chemotherapy. Variations in the type and amount of glutathione transferase in a cell can make a normal cell susceptible to cancer causing chemicals and make a cancer cell resistant to anti cancer drugs. We have discovered two new forms of glutathione transferase called Zeta and Omega. The new research to be undertaken here is aimed at understanding the role of these new enzymes in protection against foreign chemicals and the role these enzymes play in normal cellular metabolism. Because the Zeta class glutathione transferase is part of a pathway designed to eliminate excessive amounts of the amino acid tyrosine, we will determine if its inhibition will provide a new treatment for patients with a disease called hereditary tyrosinemia. We will also study the genetic and environmental factors that determine the amount of Zeta and Omega glutathione transferase produced in cellsRead moreRead less
Pharmacogenetic And Structural Investigation Of The Omega Class Glutathione Transferases
Funder
National Health and Medical Research Council
Funding Amount
$490,020.00
Summary
Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. The Omega class of glutathione transferases are important because they are involved in the metabolism of arsenic and because t ....Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. The Omega class of glutathione transferases are important because they are involved in the metabolism of arsenic and because they have been shown to influence the age-at-onset of both Alzheimer s and Parkinson s diseases. The present studies will investigate the structure and function of different Omega class glutathione transferases and determine how they interact with arsenic based drugs. These studies will attempt to determine why the toxicity of arsenic varies between individuals and aims to prevent adverse reactions to arsenic containing drugs used in cancer therapy. These studies will also investigate the mechanism by which the inheritance of certain forms of Omega class glutathione transferase can affect the age at-onset of Alzheimer s disease and Parkinson s disease. The understanding of this mechanism may provide the basis for a therapy that could delay or prevent the onset of these common diseases.Read moreRead less
The Evaluation Of Gamma-glutamylcyclotransferase As A Novel Target For Cancer Therapy And Diagnosis
Funder
National Health and Medical Research Council
Funding Amount
$433,900.00
Summary
Gamma glutamylcyclotransferase (GGCT) plays a pivotal role in regulating the synthesis of glutathione, a compound that is essential for life and regulates many intracellular processes. Several recent studies have shown that GGCT is highly expressed in cancer cells . This study will determine if GGCT is a target for cancer chemotherapy or if it can be used for cancer diagnosis. This study may also provide a new treatment for patients with glutathione synthetase deficiency.
Glutathione Transferase-derived Compounds As Therapeutic Agents
Funder
National Health and Medical Research Council
Funding Amount
$418,516.00
Summary
Inhibition of cardiac calcium ion channels may be an effective new way of improving heart performance in patients with heart failure. This project will investigate how a glutathione transferase enzyme inhibits calcium ion channels in the heart and if small fragments of a muscle specific glutathione transferase can be used to specifically modify cardiac ryanodine receptor function. These fragments will provide the basis for the development of a new therapeutic approach.
A Methylation-Based Assay For The Detection Of Prostate Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$303,712.00
Summary
Prostate Cancer is a major cause of death and morbidity among men in the western world. Little is understood of the early events that lead to the development of prostate cancer though recent evidence suggests that a modification of the DNA called methylation may be an early indictor of disease. Our current work has shown that a gene involved in the detoxification of the cell (called GST) is switched off in over 90% of prostate cancers by this DNA modification. We have studied the methylation pat ....Prostate Cancer is a major cause of death and morbidity among men in the western world. Little is understood of the early events that lead to the development of prostate cancer though recent evidence suggests that a modification of the DNA called methylation may be an early indictor of disease. Our current work has shown that a gene involved in the detoxification of the cell (called GST) is switched off in over 90% of prostate cancers by this DNA modification. We have studied the methylation pattern of the GST gene in prostate cancer and normal prostate tissue and found that the GST gene is modified exclusively in the cancer tissue . This important information has allowed us to design a test to specifically identify prostate cancer cells by assaying for GST modification . In this grant we plan to further optimise this test to ensure its sensitivity and reliability. In particular we plan to compare the effectiveness of our methylation-based test to the PSA and other tests currently used for the detection of prostate cancer. In addition we plan to identify other genes that also may be switched off specifically in prostate cancer by DNA methylation. This data will allow the development of new markers and approaches to stage the progression of prostate and possibly other cancers.Read moreRead less