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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Prostaglandin hydroperoxidase-dependent oxidation of phenylbutazone: relationship to inhibition of prostaglandin cyclooxygenase.

Prostaglandin H synthase (PHS) hydroperoxidase-mediated metabolism of phenylbutazone and the relationship of this metabolism to the inhibition of PHS cyclooxygenase by phenylbutazone was investigated. Phenylbutazone was metabolized to several intermediates and metabolites. A phenylbutazone carbon-centered radical (aN = 14.6 G) formed by PHS hydroperoxidase was trapped by 2-methyl-2-nitrosopropane and detected by ESR in incubations with ram seminal vesicle microsomes. 4-Hydroperoxy- and 4-hydroxyphenylbutazone were isolated from incubations of phenylbutazone with either ram seminal vesicle microsomes or horseradish peroxidase. Phenylbutazone (100 microM-2 mM) inhibited PHS cyclooxygenase in incubations of PHS apoenzyme reconstituted with hematin. Phenylbutazone (5-250 microM) did not inhibit PHS cyclooxygenase in incubations of PHS apoenzyme reconstituted with manganese protoporphyrin IX, which lacks hydroperoxidase activity. Thus, metabolism of phenylbutazone by PHS hydroperoxidase is required for it to inhibit PHS cyclooxygenase. 4-Hydroperoxy- and 4-hydroxyphenylbutazone were ineffective inhibitors of PHS cyclooxygenase. Other hydroperoxides that easily rearrange to peroxyl radicals were potent inhibitors of PHS cyclooxygenase, suggesting that the phenylbutazone peroxyl radical may be the inhibitor. 4-Hydroperoxyphenylbutazone was not reduced to 4-hydroxyphenylbutazone by PHS hydroperoxidase. We propose that 4-hydroxyphenylbutazone formation occurs by a nonenzymatic reaction of two phenylbutazone peroxyl radicals and their subsequent rearrangement to alkoxy radicals, which abstract hydrogen atoms. Our data indicate the importance of PHS hydroperoxidase in the inactivation of PHS cyclooxygenase by peroxides.[1]


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