Superoxide inhibition following different stimuli of respiratory burst and metabolism of aminosalicylates in neutrophils.
Reactive oxygen species such as superoxide radicals have been proposed to play an important role in the pathogenesis of inflammatory bowel disease. Some of the antiinflammatory actions of aminosalicylates have been ascribed to their capability to scavenge superoxide radicals directly or to inhibit its production in stimulated neutrophils. However, as a controversy still exists with regard to the precise mechanisms of inhibition and the metabolism within inflammatory cells, we compared scavenger properties of 5-aminosalicylic acid, 4-aminosalicylic acid, N-acetyl aminosalicylic acid, olsalazine, and benzalazine in systems with defined superoxide radical generation such as the dimethyl sulfoxide-NaOH and the potassium superoxide system. We also studied possible inhibition of the superoxide production following different stimuli of the respiratory burst in neutrophils and investigated the uptake and potential metabolism (N-acetylation) of 5-aminosalicylic acid in lipopolysaccharide-primed and resting neutrophils. We found that 5-aminosalicylic acid and 4-aminosalicylic acid had defined scavenger properties in the dimethyl sulfoxide-NaOH or potassium superoxide systems, respectively, whereas compounds with a modified aminophenolic structure had no effects. At the cellular level, 5-aminosalicylic acid inhibited phorbol myristate acetate (100 ng/ml)-activated superoxide generation to 82.3 +/- 9.3%, the formylmethionyl leucyl peptide (10(-5) M) to 61.0 +/- 6.8%, and the NaF (20 mM)-stimulated production to 32.3 +/- 3.2% (mean +/- SD, P < 0.01). The actions of the other drugs were less pronounced. Almost identical retention times (Rt = 11.2 min) of 3H-labeled phorbol myristate acetate in the presence and absence of 5-aminosalicylic acid revealed no in vitro interactions.(ABSTRACT TRUNCATED AT 250 WORDS)
Allgayer
H
H
Medical Clinic I, Klinikum Karlsruhe, Germany.
Rang
S
S
Klotz
U
U
Böhne
P
P
Retey
J
J
Kruis
W
W
Gugler
R
R
D000107:Acetylation; D010131:Aminosalicylic Acid / Q000494:pharmacology; D000636:Aminosalicylic Acids / Q000378:metabolism / Q000494:pharmacology*; D001547:Benzaldehydes / Q000494:pharmacology; D016166:Free Radical Scavengers; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D019804:Mesalamine; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D016897:Respiratory Burst / Q000502:physiology*; D013481:Superoxides / Q000037:antagonists & inhibitors*
D000636:Aminosalicylic Acids; D001547:Benzaldehydes; D016166:Free Radical Scavengers; D006835:Hydrazones; D013481:Superoxides; D019804:Mesalamine; C085292:benzalazine; D010131:Aminosalicylic Acid; C028836:N-acetyl-5-aminosalicylic acid; C032587:olsalazine