The Molecular Basis Of Cytochrome P450 And UDP-glucuronosyltransferase Isoform Substrate Selectivity
Funder
National Health and Medical Research Council
Funding Amount
$448,500.00
Summary
Drugs and chemicals (e.g. dietary constituents, environmental pollutants and industrial chemicals) are broken down in the body by specific enzymes, a process referred to as metabolism. Drug and chemical metabolism serves as a detoxification mechanism (since the end products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. Enzymes are highly specialised proteins made up from amino acids as the building blocks. There are two enzymes in ....Drugs and chemicals (e.g. dietary constituents, environmental pollutants and industrial chemicals) are broken down in the body by specific enzymes, a process referred to as metabolism. Drug and chemical metabolism serves as a detoxification mechanism (since the end products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. Enzymes are highly specialised proteins made up from amino acids as the building blocks. There are two enzymes in humans primarily responsible for the metabolism of drugs and other chemicals; cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Indeed, CYP and UGT are together responsible for the elimination of over 90% of metabolised drugs in humans. Both UGT and CYP exist as superfamilies of structurally related enzymes (called 'isoforms'). Approximately fifteen CYP isoforms are known to metabolise drugs, and a similar number of UGT isoforms also appear to have the capacity to metabolise drugs in humans. The separate CYP and UGT isoforms preferentially metabolise different types of drugs and chemicals, due to the fact each isoform comprises a different sequence of amino acids. However, which of the approximately 500 amino acids present in each UGT and CYP isoform that bind and metabolise specific drugs and chemicals is unknown. This project will identify the individual amino acids of several important CYP and UGT isoforms responsible for binding and metabolising drugs and other chemicals. A variety of techniques will be used, including modification of the amino acid sequence of the isoforms and computer modelling of their 'internal' structure. Elucidating the structural basis of how drugs and chemicals interact with CYP and UGT isoforms is fundamental to our understanding of these important enzymes and their function, and can be used to design drugs with better metabolic stability and decreased propensity for troublesome interactions with other drugs.Read moreRead less
Molecular Mechanisms Of Feed-forward Regulation Of Bile Acid Detoxification And Elimination In Cholestasis
Funder
National Health and Medical Research Council
Funding Amount
$334,500.00
Summary
Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that may of these adverse effects of obstructed bile flow are due to the retention of a component or bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic ....Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that may of these adverse effects of obstructed bile flow are due to the retention of a component or bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic and cause the death of cells within the liver if their concentration becomes too high. Evidence has emerged that the body has control mechanisms to try and combat rising levels of bile acids in cholestatic liver diseases. These control mechanisms are complex and include enzymes from the cytochrome P450 family as well as several specialized transport molecules. In cholestasis these mechanisms promote the removal of bile acids through the urine as well as converting very toxic bile acids to less toxic forms. The present projects builds on discoveries concerning the regulation of cytochrome P450 enzymes made by our group over the last few years, including an in-depth understanding of the way the production of CYP3As is increased by some drugs. We intend to determine in detail how defense mechanisms against toxic bile acids are engaged. In particular, we wish to identify the receptor molecules that 'sense' the rising levels of bile acids that occur in cholestatic liver diseases. An understanding of these issues will allow us to better manage patents with these diseases and develop new strategies for treating cholestatic disorders, for example, development of novel drugs that can influence bile acid detoxification in the liver and other organs.Read moreRead less
The Genetic Control Of Platelet Production And Function
Funder
National Health and Medical Research Council
Funding Amount
$558,920.00
Summary
Platelets are the tiny cells that circulate in the body and make blood clot. The human body has more than a trillion of them at any one time, and they are replaced every week by the blood producing cells that reside in the bone marrow. Keeping the normal number of platelets steady is incredibly important any significant drop can result in a life-threatening hemorrhage. The clinical name given to a low platelet count is thrombocytopenia, and it is a very common problem. It can be caused by geneti ....Platelets are the tiny cells that circulate in the body and make blood clot. The human body has more than a trillion of them at any one time, and they are replaced every week by the blood producing cells that reside in the bone marrow. Keeping the normal number of platelets steady is incredibly important any significant drop can result in a life-threatening hemorrhage. The clinical name given to a low platelet count is thrombocytopenia, and it is a very common problem. It can be caused by genetic mutations, viral infections, or by cancer treatments like chemotherapy. The only way to raise platelet numbers in a person with thrombocytopenia is a blood transfusion, which carries with it risks and potential side effects. While we understand quite a lot about how the body produces platelets, we don t know anywhere enough to be able to develop new treatments. Our work is focused on the identification of the genes that control the process, beginning with mouse models of thrombocytopenia, genome mapping, gene isolation, and finally, making the links between the newly identified genes and patients with thrombocytopenia. It will give us a much better understanding of how platelets are produced, how things go wrong in human disease, and how new therapies might be developed to treat them.Read moreRead less