Protection against peroxynitrite dependent tyrosine nitration and alpha 1-antiproteinase inactivation by some anti-inflammatory drugs and by the antibiotic tetracycline.
OBJECTIVE
To examine in vitro the ability of several drugs to protect against deleterious effects of peroxynitrite, a cytotoxic agent formed by reaction of nitric oxide with superoxide radical, that may be generated in the rheumatoid joint and could cause joint damage.


METHODS
The ability of several drugs to protect against such possible toxic actions of peroxynitrite as inactivation of alpha 1-antiproteinase and nitration of tyrosine was evaluated.


RESULTS
Most non-steroidal anti-inflammatory drugs were moderately (indomethacin, diclofenac, naproxen, tolmetin) or only weakly (sulindac, ibuprofen, aurothioglucose, flurbiprofen, sulphasalazine, salicylate, penicillamine disulphide) effective in preventing tyrosine nitration and alpha 1-antiproteinase inactivation by peroxynitrite, but 5-aminosalicylate and penicillamine were much more effective, as was the antibiotic tetracycline (but not ampicillin). Phenylbutazone and flufenamic acid protected effectively against tyrosine nitration, but could not be tested in the alpha 1-antiproteinase system. The analgesic paracetamol was highly protective in both assay systems.


CONCLUSIONS
Many drugs used in the treatment of rheumatoid arthritis are unlikely to act by scavenging peroxynitrite. The feasibility of peroxynitrite scavenging as a mechanism of penicillamine, 5-aminosalicylate, and paracetamol action in vivo is discussed.
Whiteman
M
M
King's College London, Pharmacology Group, London, United Kingdom.
Kaur
H
H
Halliwell
B
B
D000082:Acetaminophen / Q000494:pharmacology; D000636:Aminosalicylic Acids / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005439:Flufenamic Acid / Q000494:pharmacology; D016166:Free Radical Scavengers; D006801:Humans; D019804:Mesalamine; D009566:Nitrates / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000737:chemistry; D010396:Penicillamine / Q000494:pharmacology; D010653:Phenylbutazone / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009566:Nitrates; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D000082:Acetaminophen; D014443:Tyrosine; D019804:Mesalamine; D005439:Flufenamic Acid; D010196:Pancreatic Elastase; D013752:Tetracycline; D010653:Phenylbutazone; D010396:Penicillamine