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Biochem Pharmacol. 2000 Jan 15;59(2):153-60.

Ebselen as a peroxynitrite scavenger in vitro and ex vivo.

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Faculty of Biology, University of Konstanz, Germany.


We have previously shown that peroxynitrite (PN) selectively impaired prostacyclin (PGI2)-dependent vasorelaxation by tyrosine nitration of PGI2 synthase in an in situ model (Zou MH, Jendral M and Ullrich V, Br J Pharmacol 126: 1283-1292, 1999). By using this established model, we tested whether or not ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), which reacts rapidly with the anionic form of PN, affected PN inhibition of PGI2 synthase. Administration of ebselen (1 to 50 microM) to bovine coronary strips 5 min prior to PN (1 microM) treatment neither prevented PN-triggered vasoconstriction nor the inhibition of PGI2 release. In line with these results, ebselen affected neither PN inhibition of the conversion of [14C]-PGH2 into 6-keto-PGF1 alpha nor the nitration of PGI2 synthase in bovine aortic microsomes. Following the hypothesis that a reaction of ebselen with cellular thiols could have caused the inefficiency of ebselen, we observed that free ebselen quickly reacted with thiols in both coronary strips and in aortic microsomes to form two metabolites, one of which was identified as the ebselen-glutathione adduct, whereas the other had a similar retention time to that of the ebselen-cysteine adduct. The nitration of phenol by PN in a metal-free solution could be blocked more efficiently in the presence of ebselen or glutathione alone than in the presence of both, indicating that like selenomethionine and other selenocompounds, ebselen-thiol adducts were less reactive towards PN than ebselen itself. Further evidence came from the results that ebselen became effective in preventing the inhibition and nitration of PGI2 synthase after thiol groups of microsomal proteins were previously oxidized with Ellman's reagent. We conclude that in cellular systems ebselen is present as thiol adducts and thus loses its high reactivity towards PN, which is required to compete with the nitration of PGI2 synthase.

[Indexed for MEDLINE]

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