Interaction of myeloperoxidase with diclofenac. Inhibition of the chlorinating activity of myeloperoxidase by diclofenac and oxidation of diclofenac to dihydroxyazobenzene by myeloperoxidase.
The chlorinating activity of myeloperoxidase, isolated from human polymorphonuclear neutrophils, was inhibited by the non-steroidal anti-inflammatory drug diclofenac (Voltaren). The concentration of diclofenac needed for 50% inhibition was 20 microM, a value comparable with IC50 values found for other drugs. Diclofenac did not react with HOCl nor with H2O2 but was oxidized in the presence of myeloperoxidase and H2O2 to an orange-coloured unstable product. The rate of oxidation was proportional to the enzyme concentration and to the concentration of diclofenac. but independent of the H2O2 concentration. Presumably both Compound I and Compound II, two intermediates formed during the reaction cycle of myeloperoxidase with H2O2 are able to oxidize diclofenac. In these redox reactions, the active short-living Compound I is reduced to Compound II, thereby inhibiting the chlorinating activity of the enzyme. Analysis by Fast Atom Bombardment mass spectrometry showed that in the presence of H2O2 myeloperoxidase oxidizes diclofenac to dihydroxyazobenzene.
Zuurbier
K W
KW
E.C. Slater Institute for Biochemical Research, University of Amsterdam, The Netherlands.
Bakkenist
A R
AR
Fokkens
R H
RH
Nibbering
N M
NM
Wever
R
R
Muijsers
A O
AO
D001391:Azo Compounds / Q000737:chemistry*; D004008:Diclofenac / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry
D001391:Azo Compounds; D004008:Diclofenac; D006861:Hydrogen Peroxide; D009195:Peroxidase; C009850:azobenzene