Possible mode of action of 5-aminosalicylic acid.
Despite the extensive use of sulfasalazine (SAS) and/or 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease and, more recently, rheumatoid arthritis, their mode of action has not been elucidated so far. None of the numerous pharmacological and biochemical effects described, including immunosuppressive, antifolate, and modulatory actions on lymphocyte and leukocyte functions, could be defined unequivocally as mediating their beneficial activity. Recently, interest has focused on actions of SAS and 5-ASA on the various enzymes of the arachidonic acid cascade. Mucosa of patients with inflammatory bowel disease generates excessive amounts of cyclooxygenase products such as prostaglandins (PG) as well as 5-lipoxygenase products such as leukotriene (LT) B4 and sulfidopeptide-LT. Both PG and LT exert proinflammatory actions and are potentially important mediators of mucosal inflammation. SAS and 5-ASA, however, have been found to inhibit PG synthesis under certain experimental conditions only, while increasing PG formation under other conditions. While SAS was found to inhibit colonic LTB4 synthesis, 5-ASA was reported to selectively affect the cyclooxygenase pathway of arachidonate metabolism in this tissue. Our results demonstrate that, like the parent compound, the metabolite 5-ASA in a dose-dependent manner inhibits release of LTB4 and sulfidopeptide-LT from normal human colonic mucosa (IC50 3.5 and 3.7 mmol/liter, respectively). Indomethacin, which has no efficacy in the treatment of patients with inflammatory bowel disease, on the other hand, selectively inhibited PGE2 formation in normal and inflamed colonic mucosa (IC50 1.7 and 1.0 mmol/liter, respectively) without reducing synthesis of LTB4 or sulfidopeptide-LT.(ABSTRACT TRUNCATED AT 250 WORDS)
D000636:Aminosalicylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D003093:Colitis, Ulcerative / Q000188:drug therapy; D003424:Crohn Disease / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D017999:Leukotriene E4; D019804:Mesalamine; D012007:Rectum / Q000187:drug effects; D013189:SRS-A / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D012460:Sulfasalazine / Q000627:therapeutic use
D000636:Aminosalicylic Acids; D001095:Arachidonic Acids; D013189:SRS-A; D007975:Leukotriene B4; D016718:Arachidonic Acid; D012460:Sulfasalazine; D019804:Mesalamine; D017999:Leukotriene E4