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 representative of various NSAIDs families were tested with the chlorination of taurine used as a detection system. All were unable to inhibit taurine chlorination in a system without myeloperoxidase. In contrast, most of them induced a dose-dependent inhibition of the taurine chlorination mediated by a myeloperoxidase/H2O2/Cl- system. This took place at variable drug concentrations and IC50 were calculated. The inhibitory effect was therefore due to a direct interaction with the enzyme rather than to HOCl scavenging. A spectroscopic method used to measure the myeloperoxidase compound II lifetime in presence of the different drugs showed that all the drugs, which inhibited chlorination activity were able to induce accumulation of compound II. The extent of chlorinating activity inhibition (IC50) was inversely related to the duration of the block of enzyme in compound II form. This further demonstrates that myeloperoxidase is an interesting target for anti-inflammatory therapy. The recombinant myeloperoxidase used for the first time in this kind of study was as convenient for pharmacological purposes as the purified one.
Nève
J
J
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Free University of Brussels, Campus Plaine 205-5, B-1050, Brussels, Belgium. jneve@ulb.ac.be
Parij
N
N
Moguilevsky
N
N
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002713:Chlorine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006997:Hypochlorous Acid / Q000737:chemistry; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013654:Taurine / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011994:Recombinant Proteins; D013654:Taurine; D002713:Chlorine; D006997:Hypochlorous Acid; D009195:Peroxidase