title: Oxidation of 5-aminosalicylic acid by hypochlorous acid to a reactive iminoquinone. Possible role in the treatment of inflammatory bowel diseases.
abstract: 5-Aminosalicylic acid (5-ASA) is an agent widely used in the treatment of inflammatory bowel disease. 5-ASA has been shown to be a potential scavenger of the oxidants, such as hypochlorous acid (HOCl), that are released by neutrophils present in inflammatory bowel disease. We studied the oxidation of 5-ASA by HOCl and characterized the reaction pathway involving reactive intermediates. The reactive intermediates in the reaction of 5-ASA with HOCl were identified by use of a flow system interfaced with a Sciex API III mass spectrometer. The mass spectral analysis revealed the formation of iminoquinone and quinone reactive intermediates. The major stable product formed was identified as gentisic acid. The iminoquinone and quinone intermediates were trapped by glutathione (GSH) and the products analyzed by LC/MS. The major conjugate was formed from the quinone with one dominant isomer. In contrast, three isomers of the iminoquinone-GSH conjugates were observed in almost equal proportion. Covalent binding of the reactive intermediates to the alpha-chain of human hemoglobin was also observed. We propose that the iminoquinone is the major intermediate formed in the scavenging of neutrophil-generated HOCl by 5-ASA. Although this reaction may inactivate HOCl and be responsible for the antiinflammatory effects of the drug, it also forms reactive intermediates that covalently bind to protein and may be responsible for adverse reactions that are associated with the use of the drug.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Ontario, Canada.
authors.forename: Z C
authors.initials: ZC
authors.lastname: Liu
authors.forename: R A
authors.initials: RA
authors.lastname: McClelland
authors.forename: J P
authors.initials: JP
authors.lastname: Uetrecht
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000636:Aminosalicylic Acids / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001711:Biotransformation; D005978:Glutathione / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism* / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism*; D007700:Kinetics; D019804:Mesalamine; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000596:Amino Acids; D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006454:Hemoglobins; D011809:Quinones; D019804:Mesalamine; D006997:Hypochlorous Acid; D005978:Glutathione