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Functional analysis of mammalian epoxide hydrolases

English title Functional analysis of mammalian epoxide hydrolases
Applicant Arand Michael
Number 108326
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Pharmacology, Pharmacy
Start/End 01.06.2006 - 30.04.2010
Approved amount 479'000.00
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All Disciplines (2)

Discipline
Pharmacology, Pharmacy
Environmental Toxicology

Keywords (13)

xenobiotic metabolism; substrate selectivity; chemical carcinogenesis; physiological regulator; signalling molecule; substrate channeling; gene knock out; gene expression pattern; genotoxicity; epoxide hydrolase; toxicology; recombinant expression; blood pressure

Lay Summary (English)

Lead
Lay summary
Epoxide hydrolases are a family of enzymes that catalyze the chemical conversion of epoxides to so-called dihydrodiols by addition of water. Epoxides are a class of chemical compounds that are important for human health under two very different aspects. On the one hand, chemically reactive epoxides frequently arise in our body from the chemical conversion of foreign compounds during the attempt to convert them into better water-soluble and thus excretable products. These reactive epoxides can modify our genetic material and thereby initiate the development of tumors. Their efficient inactivation by epoxide hydrolases therefore is a protective mechanism against chemical carcinogenesis. On the other hand, epoxides derived from unsaturated fatty acids have recently evolved as important regulatory molecules that are involved in the modification of important physiological functions, in particular control of blood pressure, cell division and programmed cell death, called apoptosis. The hydrolysis of those fatty acid epoxides by epoxide hydrolases therefore influences these physiological processes. Very recently, a modulator of epoxide hydrolase activity has been subjected to clinical trials in order to characterize its potential as a new drug for plood pressure control.The aim of the present project is to characterize the role of two already known as well as three novel human epoxide hydrolases with respect to the above desribed potential functions. One part of the project is specifically dedicated to analyze their role in the control of chemical carcinogens, the other part is designed to find out more details about the general function of these enzymes in the regulation of physiological processes in the human body. The experimental approach is to cover the functional analysis from the molecular level, by directly looking at the chemical conversion of compounds by the enzyme, over the more complex situation in the context of living cells, where, among other things, protection against damage of the genetic material can be tested, up to the highest level, the intact living organism, where the influence of the enzyme activity on physiological parameters can be identified.While the project will improve our general understanding of the function of epoxide hydrolases in our organism, its particular importance for human health is based on the fact that these enzymes are now target for drug therapy. It is of great importance importance to understand as much as possible about the physiological function of a new drug target, in order to forsee and circumvent undesired side effects of the new medication.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
146635 Deciphering the (patho)physiologic role of epoxide hydrolases by ex vivo cartography of their substrate landscape 01.02.2014 Project funding
146635 Deciphering the (patho)physiologic role of epoxide hydrolases by ex vivo cartography of their substrate landscape 01.02.2014 Project funding

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