title: Scavenging effect of 5-aminosalicylic acid on neutrophil-derived oxidants. Possible contribution to the mechanism of action in inflammatory bowel disease.
abstract: 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.
authors.affiliation: Gastrointestinal Diseases Research, Searle Research and Development, Skokie, IL 60077.
authors.forename: H
authors.initials: H
authors.lastname: Tamai
authors.forename: J F
authors.initials: JF
authors.lastname: Kachur
authors.forename: M B
authors.initials: MB
authors.lastname: Grisham
authors.forename: T S
authors.initials: TS
authors.lastname: Gaginella
mesh_terms: 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
chemical_list: D000636:Aminosalicylic Acids; D000975:Antioxidants; D016166:Free Radical Scavengers; D000643:Ammonium Chloride; D019804:Mesalamine; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D003545:Cysteine