Mechanism of inhibition of myeloperoxidase by anti-inflammatory drugs.
Hypochlorous acid (HOCl) is the most powerful oxidant produced by human neutrophils, and should therefore be expected to contribute to the damage caused by these inflammatory cells. It is produced from H2O2 and Cl- by the heme enzyme myeloperoxidase (MPO). We used a H2O2-electrode to assess the ability of a variety of anti-inflammatory drugs to inhibit conversion of H2O2 to HOCl. Dapsone, mefenamic acid, sulfapyridine, quinacrine, primaquine and aminopyrine were potent inhibitors, giving 50% inhibition of the initial rate of H2O2 loss at concentrations of about 1 microM or less. Phenylbutazone, piroxicam, salicylate, olsalazine and sulfasalazine were also effective inhibitors. Spectral investigations showed that the inhibitors acted by promoting the formation of compound II, which is an inactive redox intermediate of MPO. Ascorbate reversed inhibition by reducing compound II back to the active enzyme. The characteristic properties that allowed the drugs to inhibit MPO reversibly were ascertained by determining the inhibitory capacity of related phenols and anilines. Inhibition increased as substituents on the aromatic ring became more electron withdrawing, until an optimum reduction potential was reached. Beyond this optimum, their inhibitory capacity declined. The best inhibitor was 4-bromoaniline which had an I50 of 45 nM. An optimum reduction potential enables inhibitors to reduce MPO to compound II, but prevents them from reducing compound II back to the active enzyme. Exploitation of this optimum reduction potential will help in targeting drugs against HOCl-dependent tissue damage.
Kettle
A J
AJ
Department of Pathology, Christchurch School of Medicine, New Zealand.
Winterbourn
C C
CC
D062365:Aminobenzoates / Q000378:metabolism; D000636:Aminosalicylic Acids / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003622:Dapsone / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D019804:Mesalamine; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D010636:Phenols / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology
D062365:Aminobenzoates; D000636:Aminosalicylic Acids; D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010636:Phenols; D019804:Mesalamine; D006997:Hypochlorous Acid; D003622:Dapsone; D006861:Hydrogen Peroxide; D009195:Peroxidase; D011796:Quinacrine