Toshiaki Miura1. 1. Department of Biology, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan. miurat@hokuyakudai.ac.jp
Abstract
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.
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.