TY - JOUR T1 - Prostaglandin H synthase: perturbation of the tyrosyl radical as a probe of anticyclooxygenase agents. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 833 LP - 837 VL - 40 IS - 5 AU - R J Kulmacz AU - G Palmer AU - A L Tsai Y1 - 1991/11/01 UR - http://molpharm.aspetjournals.org/content/40/5/833.abstract N2 - EPR spectroscopy was used to study the effects of various nonsteroidal anti-inflammatory agents on the peroxidase-related tyrosyl radical present in prostaglandin H synthase (prostaglandin endoperoxide synthase; EC 1.14.99.1). Two types of perturbation of the tyrosyl radical by these anticyclooxygenase agents were observed. In the first case, aspirin, indomethacin, ibuprofen, (S)-flurbiprofen, and (S)-naproxen converted the doublet tyrosyl EPR signal seen on reaction of the uninhibited enzyme with ethyl hydroperoxide to a singlet bearing additional partially resolved hyperfine splittings. These compounds also decreased the maximum amount of radical generated, but they did not change the kinetics of formation and decay of the tyrosyl radical. In the second case, acetaminophen and three fenamate analogs (meclofenamate, flufenamate, and mefenamate) did not perturb the EPR line shape observed after reaction with hydroperoxide but did cause a more rapid decay of the tyrosine radical species. It would appear that, despite considerable variation in structure, the nonsteroidal anti-inflammatory agents may inhibit the cyclooxygenase activity of the synthase by two basic mechanisms. ER -