Promotion of oxidative damage to arachidonic acid and alpha 1-antiproteinase by anti-inflammatory drugs in the presence of the haem proteins myoglobin and cytochrome C.
A mixture of myoglobin and hydrogen peroxide (H2O2) causes peroxidation of arachidonic acid. This peroxidation is greatly accelerated by adding phenylbutazone, which is effective even in the absence of H2O2. A wide range of other drugs was examined for their ability to exert similar pro-oxidant effects. We found that meclofenamic acid and flufenamic acid stimulated myoglobin-dependent lipid peroxidation, but only in the presence of H2O2. Ascorbic acid inhibited peroxidation both in the presence and in the absence of these drugs. Phenylbutazone, meclofenamic acid and flufenamic acid could also cause damage to proteins (as measured by inactivation of alpha 1-antiproteinase) in the presence of myoglobin and H2O2. The mitochondrial protein cytochrome c can also stimulate lipid peroxidation in the presence of H2O2. Phenylbutazone and meclofenamic acid, but not flufenamic acid, enhanced the peroxidation, which was again inhibited by ascorbic acid. However, only phenylbutazone caused inactivation of alpha 1-antiproteinase in the presence of cytochrome c and H2O2. Since respiring mitochondria generate superoxide radicals and H2O2, catalysis of lipid peroxidation and of the formation of drug-derived radicals by cytochrome c could be a mechanism contributing to mitochondrial damage by drugs.
Evans
P J
PJ
Pharmacology Group, University of London King's College, U.K.
Akanmu
D
D
Halliwell
B
B
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000737:chemistry*; D001205:Ascorbic Acid / Q000494:pharmacology; D003574:Cytochrome c Group / Q000494:pharmacology*; D004357:Drug Synergism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D009211:Myoglobin / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010653:Phenylbutazone / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000737:chemistry*
D000893:Anti-Inflammatory Agents; D003574:Cytochrome c Group; D009211:Myoglobin; D000515:alpha 1-Antitrypsin; D016718:Arachidonic Acid; D006861:Hydrogen Peroxide; D010653:Phenylbutazone; D001205:Ascorbic Acid