Molecular Mechanisms Of Human Cytochrome P450 CYP3A4 Gene Regulation
Funder
National Health and Medical Research Council
Funding Amount
$196,059.00
Summary
Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. Cytochrome P450 3A4 (CYP3A4) is arguably the single most important factor is how humans handle therapeutic drugs. It has been estimated that over 60% of all ....Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. Cytochrome P450 3A4 (CYP3A4) is arguably the single most important factor is how humans handle therapeutic drugs. It has been estimated that over 60% of all drugs presently on the market are broken down, either in full or in part, by this enzyme. The amounts of CYP3A4 expressed in the liver differs markedly between individuals, and explains a great deal of the large variation in the way people break down drugs. Also, variations in the levels of CYP3A4 in the liver may be an important factor in both prostate cancer (the most common cancer in men) and the risk of developing leukemia after receiving chemotherapy for other cancers. 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 CYP3A4 is increased by some drugs. In this project we seek to understand why individuals differ so much in terms of the amount of CYP3A4 in the liver (up to 10-fold) and why this enzyme is predominantly expressed in the liver and to as lesser extent, the intestine, while not being found at all in many other tissues. An understanding of these issues will allow us to: Y predict how patients will respond to drugs (pharmacogenetic testing). Y determine susceptibility to certain diseases (e.g., prostate cancer). Y develop novel drugs that can influence CYP3A4 production in the liverRead moreRead less
Metabotropic Glutamate Receptors: Pharmacological Studies Of Receptor Subtypes In Neuronal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$145,770.00
Summary
Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexp ....Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexplored and is the topic under investigation in this project. How their activation affects cellular signaling switch on will be investigated to gain an understanding of the roles metabotropic glutamate receptors play in acute brain injury (eg stroke) and chronic neurodegenerative conditions (eg Huntington's chorea and Alzheimer's disease).Read moreRead less