Role Of Flavonoids From Phytomedicines In Herb-Drug Interactions Mediated By P-glycoprotein
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
The herbal therapeutics St John's wort and Ginkgo biloba are used by cancer patients to alleviate symptoms of psychic disturbances associated with their condition. The possibility of interactions between flavonoid components of these herbs and anticancer treatment will be examined. Resistance to cancer chemotherapy often develops due to overexpression of the drug transporter P-glycoprotein (P-gp). Investigation of the interaction of the flavonoid components of herbal preparations and P-gp will e ....The herbal therapeutics St John's wort and Ginkgo biloba are used by cancer patients to alleviate symptoms of psychic disturbances associated with their condition. The possibility of interactions between flavonoid components of these herbs and anticancer treatment will be examined. Resistance to cancer chemotherapy often develops due to overexpression of the drug transporter P-glycoprotein (P-gp). Investigation of the interaction of the flavonoid components of herbal preparations and P-gp will establish whether the flavonoids alter the outcome of chemotherapy in resistant cancers in the short term. We will also examine whether exposure to flavonoids in herbal medicines and diets rich in flavonoids from fruit and vegetables affects development and progress of multidrug resistance over the long term.Read moreRead less
Structure And Gene Regulation Of Human Glutathione Transferase GSTT1-1
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Glutathione transferases (GSTs) play a critical role cellular detoxification system. They belong to the phase II enzymes of the xenobiotic metabolism and conjugate a wide range of drugs and chemicals with glutathione to increase water solubility and thereby enhancing their elimination. The conjugation with glutathione is considered an important detoxification route for most chemicals. However, it has been shown that in many cases this pathway leads to metabolites that are more toxic than the ini ....Glutathione transferases (GSTs) play a critical role cellular detoxification system. They belong to the phase II enzymes of the xenobiotic metabolism and conjugate a wide range of drugs and chemicals with glutathione to increase water solubility and thereby enhancing their elimination. The conjugation with glutathione is considered an important detoxification route for most chemicals. However, it has been shown that in many cases this pathway leads to metabolites that are more toxic than the initial chemical or drug. The gene deletion of the particular human GSTT1 gene results in total loss of this particular enzyme activity in all tissues of homozygous null genotype individuals. This phenotype is called non-conjugator . Non-conjugators seem to have a higher risk to develop certain cancer types, e.g. urinary bladder cancer or brain tumours, while they seem to be less susceptible for others, e.g. liver. Occupational exposure to chemicals is of relevance in such relationships because the GSTT1 enzyme metabolises a wide range of industrial chemicals including solvents but also monomers used in the production of rubbers and other polymers. In addition, GSTT1 seems to influence the efficay of cancer chemotherapy by inactivating certain anti-cancer drugs, eg. BCNU, that is predominantly use in treatment of brain tumours. The aims of this study include the characterisation of the tissue-specific activity and the influence of xenobiotics on the protein levels of this enzyme. The study leads to a better understanding of the etiology of exposure related cancers and of the mechanisms of resistance to cancer chemotherapy. Such knowledge allows the development of concepts for the optimisation of efficacy and minimisation of side effects in chemotherapy.Read moreRead less
Structure, Function And Regulation Of Human Cytosolic Sulfotransferases
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
The sulfotransferase family of enzymes serve an important role in the metabolism of drugs and foreign chemicals. They also metabolise a range of chemicals that are normally present in the body such as hormones and substances that are involved in brain function (neurotransmitters). Observations from clinical studies suggest that differences in sulfotransferases activities may be a causal factor in the incidence of certain types of cancer and neurodegenerative diseases. Recent advances in understa ....The sulfotransferase family of enzymes serve an important role in the metabolism of drugs and foreign chemicals. They also metabolise a range of chemicals that are normally present in the body such as hormones and substances that are involved in brain function (neurotransmitters). Observations from clinical studies suggest that differences in sulfotransferases activities may be a causal factor in the incidence of certain types of cancer and neurodegenerative diseases. Recent advances in understanding the molecular biology of these enzymes have shown us that multiple forms of sulfotransferase existed within the body. In this area my laboratory has been at the forefront of the cloning and characterisation of these enzymes. Indeed, we were the first laboratory to clone the major human sulfotransferase (SULT1A3) responsible for the metabolism of brain neurotransmitters. We have also used new technology to determine the shape of this important enzyme. At the time of writing my laboratory has characterised a total seven human sulfotransferases but unlike SULT1A3, our knowledge of the functional significance of the other six sulfotransferase is poorly understood. Further, our knowledge of what regulates the amount of sulfotransferase in different tissues is practically nonexistent. The thrust of this project is to extend our studies on the physiological function of these enzymes and also through the use of molecular biology techniques understand what controls the level of their expression in different human tissues. This knowledge will provide a basis for understanding the role of sulfotransferases play in drug and chemical metabolism. It will also aid our understanding of their role in hormone and neurotransmitter metabolism and help determine whether they are involved in such diseases as cancer and neurodegenerative diseases.Read moreRead less
Reducing Deaths From Pesticide Poisoning - Establishing A Regional Toxicology Research Centre.
Funder
National Health and Medical Research Council
Funding Amount
$739,727.00
Summary
The World Health Organization estimates suggest nearly half a million people die from acute pesticide poisoning in the Asia-Pacific region each year. The Sri Lankan project will be the first attempt to systematically test whether a range of strategies can reduce long-term neurological damage and deaths from pesticides. The Australian-Sri Lankan Collaboration will, over the next five years, aim to improve assessment of sub-acute and long-term morbidity; promote 'evidence-based' treatment; develop ....The World Health Organization estimates suggest nearly half a million people die from acute pesticide poisoning in the Asia-Pacific region each year. The Sri Lankan project will be the first attempt to systematically test whether a range of strategies can reduce long-term neurological damage and deaths from pesticides. The Australian-Sri Lankan Collaboration will, over the next five years, aim to improve assessment of sub-acute and long-term morbidity; promote 'evidence-based' treatment; develop new antidotes (and assess their cost effectiveness), and see if pesticide regulation can reduce the rate of severe or fatal poisoning. If successful, this program may become a model for the region as to how to substantially reduce this largely hidden tragedy.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.
This application will investigate the potential for nanomaterials to have adverse effects on human health and to formulate approaches to screen nanomaterials for potential health risks, particularly those with a high likelihood for human exposure in Australia. Understanding how existing nanomaterials interact with biological systems will help determine the risk of adverse effects in the human population and identify those nanoparticles with little or no risk.
Cellular Ageing: Is the Plasma Membrane the Control Hub? This project aims to determine whether the plasma membrane lipid composition is a major driver of cellular ageing. It expects to generate new knowledge in the molecular mechanism of cellular ageing, utilising our team’s deep expertise in lipid biology, bioinformatics, biophysics, extracellular vesicle biology and cellular ageing. Expected outcomes include the identification of novel cellular ageing markers and anti-ageing targets while als ....Cellular Ageing: Is the Plasma Membrane the Control Hub? This project aims to determine whether the plasma membrane lipid composition is a major driver of cellular ageing. It expects to generate new knowledge in the molecular mechanism of cellular ageing, utilising our team’s deep expertise in lipid biology, bioinformatics, biophysics, extracellular vesicle biology and cellular ageing. Expected outcomes include the identification of novel cellular ageing markers and anti-ageing targets while also cementing long-standing partnerships and fostering new interdisciplinary collaborations. This cellular ageing study will provide novel insights into the basic principles of cellular behaviour, e.g. growth, differentiation, communication and death, reinforcing Australia’s leadership in biological science.Read moreRead less
Androgen receptor: A master regulator of lipid metabolism. This project aims to understand how male sex hormones, or androgens, affect the amount and metabolism of fats in normal body tissues. By integrating our multi-disciplinary expertise in androgen action, molecular biology, metabolism and bioinformatics with novel techniques and instrumentation, this collaboration expects to generate the first detailed picture of how fat metabolism is controlled by androgens in humans, and how closely this ....Androgen receptor: A master regulator of lipid metabolism. This project aims to understand how male sex hormones, or androgens, affect the amount and metabolism of fats in normal body tissues. By integrating our multi-disciplinary expertise in androgen action, molecular biology, metabolism and bioinformatics with novel techniques and instrumentation, this collaboration expects to generate the first detailed picture of how fat metabolism is controlled by androgens in humans, and how closely this relates to mice. Expected outcomes and benefits will be a new understanding of which aspects of fat metabolism are most influenced by androgens, and an ability to anticipate potential metabolic impacts of natural or pharmacological fluctuations in androgen levels in humans, laboratory animals and livestock.Read moreRead less