Effects of BX661A, a new therapeutic agent for ulcerative colitis, on reactive oxygen species in comparison with salazosulfapyridine and its metabolite sulfapyridine.
5-[4-(2-Carboxyethylcarbamoyl)phenylazo]salicylic acid disodium salt dihydrate (CAS 80573-04-2, BX661A) is developed as a therapeutic agent for ulcerative colitis. To clarify its mechanism of action, the effects of BX661A and its metabolites 5-aminosalicylic acid (5-ASA) and 4-aminobenzoyl-beta-alanine (4-ABA) on reactive oxygen species: superoxide radicals (O2-) generated by hypoxanthine and xanthine oxidase, hydrogen peroxide (H2O2), hypochlorite radicals (OCl-) and hydroxyl radicals (OH.), were investigated and compared with the effects of 2-hydroxy-5-[[4-[(2-pyridinylamino)sulfonyl]phenyl]azo]-benzoic acid (CAS 599-79-1, salazosulfapyridine, SASP) and its metabolite 4-amino-N-2-pyridinyl-benzenesulfonamide (CAS 144-83-2, sulfapyridine, SP). 1. BX661A, SASP and 5-ASA inhibited O2- radical production in a concentration-dependent manner (IC50 = 0.14, 0.13 and 0.19 mmol/l, respectively). The effects of 4-ABA and SP on O2- radical production were weak (IC50 = > 10 and > 3 mmol/l, respectively). In contrast, superoxide dismutase inhibited O2- radical production in a concentration-dependent manner (IC50 = 1.7 U/ml). 2. BX661A, SASP, 4-ABA and SP had no H2O2 scavenging effects. 5-ASA scavenged H2O2, but its maximal scavenging action was 51.3%. In contrast, catalase scavenged H2O2 in a concentration-dependent manner (IC50 = 0.47 U/ml). 3. BX661A, SASP and 5-ASA scavenged OCl- radicals in a concentration-dependent manner (IC50 = 69.5, 73.8 and 21.7 mumol/l, respectively). 4-ABA and SP had no OCl- radical scavenging effects. In contrast, nordihydroguaiaretic acid (NDGA) scavenged OCl- radicals in a concentration-dependent manner (IC50 = 8.7 mumol/l). 4. BX661A and SASP scavenged OH. radicals in a concentration-dependent manner; the maximal scavenging values were 39.5 (10 mmol/l) and 48.6% (3 mmol/l), respectively. 4-ABA and SP had no OH. radical scavenging effects. In contrast, 5-ASA scavenged OH. radical in a concentration-dependent manner (IC50 = 1.46 mmol/l). These results suggest that BX661A has O2- and OCl- radical scavenging effects and that 5-ASA has O2-, OCl- and OH. radical scavenging effects. Therefore, these effects may be partially involved in the therapeutic effects of BX661A on ulcerative colitis.
Kimura
I
I
Medical Information and Development Division, Hoechst Marion Roussel Ltd., Saitama, Japan.
Kumamoto
T
T
Matsuda
A
A
Kataoka
M
M
Kokuba
Y
Y
D000636:Aminosalicylic Acids / Q000737:chemistry* / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000737:chemistry* / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000188:drug therapy; D003574:Cytochrome c Group / Q000378:metabolism; D006861:Hydrogen Peroxide; D006997:Hypochlorous Acid; D007700:Kinetics; D019804:Mesalamine; D010659:Phenylhydrazines; D017382:Reactive Oxygen Species; D013427:Sulfapyridine / Q000494:pharmacology*; D012460:Sulfasalazine / Q000494:pharmacology*; D013481:Superoxides
D000636:Aminosalicylic Acids; D000897:Anti-Ulcer Agents; D003574:Cytochrome c Group; D010659:Phenylhydrazines; D017382:Reactive Oxygen Species; D013481:Superoxides; D012460:Sulfasalazine; D019804:Mesalamine; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; C038637:balsalazide; D013427:Sulfapyridine