Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs investigated with a human recombinant enzyme

Non-steroidal anti-inflammatory drugs (NSAIDs) were investigated for their ability to affect the chlorinating activity of human myeloperoxidase and to scavenge HOCl, the main myeloperoxidase system product. Fourteen drugs rep resentative of various NSAIDs families were tested with the chlorination of taurine used as a detection system. All were unable to inhibit taurine chl orination in a system without myeloperoxidase. In contrast, most of them in duced a dose-dependent inhibition of the taurine chlorination mediated by a myeloperoxidase/H2O2/Cl- system. This took place at variable drug concentr ations and TCS, were calculated. The inhibitory effect was therefore due to a direct interaction with the enzyme rather than to HOCl scavenging. A spe ctroscopic method used to measure the myeloperoxidase compound II lifetime in presence of the different drugs showed that all the drugs, which inhibit ed chlorination activity were able to induce accumulation of compound II. T he extent of chlorinating activity inhibition (ICS,) was inversely related to the duration of the block of enzyme in compound II form. This further de monstrates that myeloperoxidase is an interesting target for anti-inflammat ory therapy. The recombinant myeloperoxidase used for the first time in thi s kind of study was as convenient for pharmacological purposes as the purif ied one. (C) 2001 Elsevier Science B.V. All rights reserved.