Degradation of Agricultural and Natural Toxins Present in Livestock Feed and Forage

NON-TECHNICAL SUMMARY: We focus on enzymes that degrade a large number of foreign compounds including toxins common in feed and forage. Thus study of these enzymes may lead to improved veterinary care of livestock species. The development of rapid methods for the identification of foreign compounds in feed and forage is essential to ensure the safety of livestock species and protect human health as well. <P>

APPROACH: Approach I. Purify, clone and characterize esterases and epoxide hydrolases from model and livestock species. Determine substrate selectivity for endogenous and exogenous compounds. Determine inhibitor profile and predict if exposure to foreign compounds in feed and forage could lead to toxicity. Approach II. Using existing antibodies format existing assays for higher sensitivity, lower cost, and ease of use using novel reporters such as europium nanoparticles. Employ novel biosensor formats such as microdroplet and microfluidics to improve assays. Develop new assays to materials considered to pose risk to livestock species or materials that are likely contaminants of feed, forage, and food products.

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PROGRESS: 2003/10 TO 2008/09 <BR>
OUTPUTS: I will emphasize the results over the last year in this narrative of the terminal report of this project. We had 27 peer reviewed papers published during the terminal year of this project. This project has been leveraged to bring millions of dollars in research funds to the campus during its life in areas related to human and animal health primarily from the NIH institutes dealing with environmental chemistry, diabetes and metabolism, and cardiovascular disease in addition to other sources. The laboratory was also supported last year by the Dairy Board. Among other things we established the soluble epoxide hydrolase (sEH)as a target for action of environmental chemicals including chemicals used in dairy production. On the positive side we established the enzyme as a target for the development of drugs for both animal and human health. In the last year we determined the upstream regulatory regions for the sEH gene showing that it is regulated by ppar agonists and angiotensin. This demonstrates that the sEH is intimately involved in the RAAS system of blood pressure regulation. We demonstrated that as predicted at the molecular level that sEH inhibitors (sEHI) can control blood pressure and block and reverse heart failure. We also demonstrated that they block atherosclerosis. A surprise was finding that sEHI are strongly analgesic with inflammatory and neuropathic pain. This work has been disseminated in peer reviewed publication. It is on the net at medical sites for cardiovascular disease, diabetes, obesity and others, it has been cited in newspapers and a general interest article was put out on this work by the USDA. <BR> PROJECT MODIFICATIONS: The project is being terminated because we have received no direct resources for a number of years and have other experiment station projects. The paper work to support ratio approached an infinite level.
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IMPACT: 2003/10 TO 2008/09 <BR>
A compound developed with this project is in phase II clinical trials to treat hypertension in obese diabetics. This is one of the few examples of an investigational new drug candidate being optimized and synthesized in an academic laboratory before being transferred to industry for development. The University of California over the objections of the inventors licensed veterinary rights to a company with no interest in veterinary drugs. We have been working to circumvent our own patents to full fill our obligations to the agricultural experiment station. This is a first in class drug which could have a major impact on human health. It reduces high blood pressure and blocks heart failure and hardening of the arteries by a common and unique mechanism. By a different mechanism it synergizes the action of NSAIDs such as advil, celebrex, indomethacin, and aspirin and reduces their side effects.