Reactivity of nonsteroidal anti-inflammatory drugs with peroxidase: a classification of nonsteroidal anti-inflammatory drugs

Objectives To improve understanding of the essential effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on prostaglandin H synthase (PGHS), the reactivity of NSAIDs with peroxidases and the tyrosyl radical derived from myoglobin was examined. Methods Horseradish peroxidase and myoglobin were used as models of peroxidase and cyclooxygenase of PGHS, respectively. Key findings From the results, a new classification of NSAIDs has been proposed. Class 1 includes the majority of NSAIDs, which reacted with horseradish peroxidase compound I, thus causing a spectral change by PGHS peroxidase and also including diminished electron spin resonance signals of the tyrosyl radical of myoglobin. They reduced compound I of horseradish peroxidase and scavenged the tyrosyl radical. The branched-chain mechanism by which the porphyrin radical is transferred to the tyrosine residue of the protein might be blocked by these NSAIDs. Class 2 includes salicylic acid derivatives that reacted only with the porphyrin radical and not with horseradish peroxidase compound II (oxoferryl species). Class 3 includes aspirin, nimesulide, tolmetin, and arylpropionic acid derivatives, including ibuprofen and the coxibs of celecoxib and rofecoxib, which are not substrates for horseradish peroxidase or PGHS peroxidase. Conclusions Understanding the essential mode of action of NSAIDs is particularly important for designing an effective therapeutic strategy against inflammatory diseases.