Scavenging effect of 5-aminosalicylic acid on neutrophil-derived oxidants. Possible contribution to the mechanism of action in inflammatory bowel disease.
Inflammatory phagocytic leukocytes produce superoxide and hydrogen peroxide and secrete myeloperoxidase (MPO) into the extracellular medium. MPO catalyzes the oxidation of Cl- by H2O2 to yield chlorinated oxidants (e.g. HOCl and NH2Cl), which have been shown to induce pathologic changes in mucosal function. We examined the ability of 5-aminosalicylic acid (5-ASA), a drug used to treat inflammatory bowel disease (IBD), to inhibit oxidation of L-cysteine by NH2Cl, HOCl and H2O2. NH2Cl and HOCl were especially strong oxidants against L-cysteine. 5-ASA prevented L-cysteine oxidation by NH2Cl and HOCl; an interaction associated with the formation of characteristic absorption spectra due to the oxidation of 5-ASA was observed. NH2Cl and HOCl evoked characteristic increases in short-circuit current (Isc), indicative of net electrolyte transport, when added to the serosal side of stripped rat colon mounted in Ussing chambers. Premixing of NH2Cl with 5-ASA 10 min before addition to the tissue markedly reduced the secretory response to NH2Cl. In contrast, 5-ASA immediately reduced the response to HOCl. The reduction in the functional response to NH2Cl and HOCl by 5-ASA may contribute to its mechanism of action in the treatment of the symptoms of IBD.
Tamai
H
H
Gastrointestinal Diseases Research, Searle Research and Development, Skokie, IL 60077.
Kachur
J F
JF
Grisham
M B
MB
Gaginella
T S
TS
D000636:Aminosalicylic Acids / Q000494:pharmacology*; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D008297:Male; D019804:Mesalamine; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000636:Aminosalicylic Acids; D000975:Antioxidants; D016166:Free Radical Scavengers; D000643:Ammonium Chloride; D019804:Mesalamine; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D003545:Cysteine