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Discovery of N-hydroxyguanidines as novel electron acceptors of xanthine oxidase: Potential new drugs for treatment of ischemia and reperfusion injury
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Xanthine oxidase (EC 1.1.3.22) is one of the major enzymatic sources of oxygen-derived free radicals. It is thought to cause a number of serious clinical disorders, including the reperfusion injury following a period of ischemia. The present study describes the discovery of a new possibility to inhibit superoxide radical formation by using N-hydroxyguanidine compounds, which act as alternative electron acceptors of xanthine oxidase.

Earlier it was observed that, in radioligand binding assays, the N-hydroxyguanidine compound guanoxabenz, bound to α2-adrenoceptors with two different apparent affinities in certain rat tissue membranes. We found that the formation of high affinity binding for guanoxabenz is dependent on the generation of a metabolite, guanabenz, which has a greater affinity for the α2-adrenoceptors than guanoxabenz itself. The guanoxabenz-reducing enzyme was purified from rat spleen cytosol. The activity could be inhibited by allopurinol, or sustained by NADH or xanthine as co-factors. Amino acid sequencing showed that the enzyme was identical with xanthine oxidase. However, in addition to xanthine oxidase other, as yet unidentified, guanoxabenz-reducing activity was found in rat brain membranes.

A series of N-hydroxyguanidines were synthesized and tested for xanthine oxidase electron acceptor activity. The greatest electron acceptor activity was seen in compounds where the guanidine fragment is conjugated with a benzene ring having π-donating substituents in paraposition. The electron density on the guanidine fragment leads to the increase in electron acceptor activity.

Mechanistic studies have indicated that N-hydroxyguanidine derivative PR5 binds to xanthine oxidase and becomes reduced at the molybdenum centre of the enzyme. PR5 was also found to be both an electron acceptor and an inhibitor of xanthine oxidase, both effects attenuating superoxide formation.

In an in vivo rat myocardial infarction model, the N-hydroxyguanidine derivative PR5 was shown to provide remarkable protection against ischemia and reperfusion-induced myocardial necrosis and life-threatening arrhythmia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 51 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 217
Keyword [en]
Pharmaceutical biosciences, xanthine oxidase, N-hydroxyguanidine derivatives, ischemia and reperfusion, reduction, inhibition, superoxide
Keyword [sv]
Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-384ISBN: 91-554-4575-6 (print)OAI: oai:DiVA.org:uu-384DiVA: diva2:163779
Public defence
1999-11-19, lecture hall B41, Biomedical Center, Uppsala, Uppsala, 09:15
Available from: 1999-10-29 Created: 1999-10-29Bibliographically approved

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