Hyperuricemia is the hallmark of gout. Pathogenic mechanisms of hyperuricemia include uric acid overproduction in the liver or underexcretion in the kidney. Current antihyperuricemic agents include xanthine oxidase inhibitors in which allopurinol is the most often prescribed. Inhibitors of renal urate reabsorption such as probenecid and benzbromarone are also employed. However, these existing antihyperuricemic agents possess some undesirable effects such as hypersensitivity towards allopurinol and hepatotoxicity associated with benzbromarone. Therefore, search for alternative antihyperuricemic agents with a more favorable toxicological profile or via mechanisms other than the above two mentioned is highly warranted. / The present project represents such an effort. Four in vitro experimental models were developed for the screening of new antihyperuricemic agents. The effects of the potential compounds from natural sources on the activities of phosphoribosyl pyrophosphate synthetase, hypoxanthine-guanine phosphoribosyl transferase and xanthine oxidase, as well as the uptake of urate through rat renal brush border membrane vesicles were investigated. Several compounds emerged with strong urate uptake inhibitory activities in which morin (3, 5, 7, 2', 4'-pentahydroxyflavone) was the most potent. Interestingly some of these compounds including morin were also demonstrated to be xanthine oxidase inhibitors. The subsequent in vivo experiment showed that morin indeed exhibited hypouricemic and uricosuric actions in an acute oxonate-induced hyperuricemic rat model. The uricosuric action of morin was hirther studied in transfected HEK293 cells expressing the human urate anion transporter 1 (hURATI) which is believed to regulate blood urate level by mediating urate reabsorption. In hURAT1-expressing HEK293 cells, urate uptake was significantly increased as compared to the non-transfected parental cells. Incorporation of morin into the uptake buffer could dose-dependently inhibit urate uptake in the transfected cells. Taken together our data indicated that morin is a potentially useful antihyperuricemic agent which acts by inhibiting xanthine oxidase and inhibiting urate reabsorption. In addition, the favorable safety profile of this natural compound makes it a potential candidate worthy of further investigations. / Yu Zhifeng. / "June 2006." / Advisers: Christopher H. K. Cheng; Wing Ping Fong. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1584. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 155-169). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_343906 |
| Date | January 2006 |
| Contributors | Yu, Zhifeng., Chinese University of Hong Kong Graduate School. Division of Biochemistry. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xv, 169 p. : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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