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
The Role Of The Gastric H/K ATPase In Parietal Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$166,885.00
Summary
The cells of the body contain many specialised membrane structures. At present it is not clear how the synthesis of these stuctures is directed. To study this problem we are examining the acid secretory parietal cells of the stomach. These cells have a very elaborate membrane system that contains a major proton pump protein. By manipulating the levels and form of the proton pump we will gain novel insights into the mechanism of membrane structure and function.
Proton translocating ATPases are central to biological energy conversion, one of the most fundamental biological processes on earth whose elucidation has already led to several Nobel prizes. Synthesis of the universal biological energy carrier ATP takes place in the well-characterised soluble domain. The focus of this study is to understand the unknown function of the proton-driven transmembrane motor, which will give fundamental new insights into biological energy conversion and its regulation.
We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a ....We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a body of evidence that suggests the following interactions between inflammatory cytokines and salicylate, with important practical ramifications, in children. 1. Salicylate toxicity, like the acute multi-organ form of childhood malaria it mimics, is probably caused by excess systemic iNOS induction. This plausibly includes the metabolic acidosis, hypoglycaemia, seizures, coma and cerebral oedema seen in both conditions. Both are thus logically susceptible to treatment with specific iNOS inhibitors. 2. The same picture would arise in children when smaller doses of salicylate synergise with IFN-g, IL-1b, and perhaps other cytokines induced by malaria as well as by viruses. This gives the first proposed explanation for Reye's syndrome, defining the circumstances in which it occurs, and predicting a rationale for its treatment. Through the parallels seen in different age groups in malaria and aspirin toxicity, it also rationalises the difference in childhood vs adult malaria syndromes. 3. The overall severity and mortality of childhood malaria in East Africa may be worsened, through this cytokine-salicylate synergy, by home treatment with aspirin when children first become ill. 4. A relative absence of salicylate intake by children in various malarial Pacific Islands may contribute to falciparum malaria being a less severe disease there than in East Africa.Read moreRead less