title: A molecular mechanism for the anti-inflammatory effect of taurine-conjugated 5-aminosalicylic acid in inflamed colon.
abstract: In previous reports, a novel colon-specific prodrug, 5-aminosalicyltaurine (5-ASA-Tau) administered orally, is successfully delivered to and liberates 5-aminosalicylic acid (5-ASA) and taurine in the inflamed large intestine of rats. Furthermore, the prodrug ameliorates the 2,4,6-trinitrobenzene-sulfonic acid-induced colitis, and taurine acts not only as a carrier but also as an active therapeutic agent. In this study, we investigated the anti-inflammatory properties of the prodrug at a molecular level. After rectal administration of taurine, formation of taurine chloramine (TauCl) in the inflamed colonic tissue was examined using high-performance liquid chromatography. In human colon epithelial cell lines, nuclear factor-kappaB (NF-kappaB) activity was accessed using an NF-kappaB-dependent luciferase reporter gene. Protein levels were monitored by Western blotting. DNA binding activity of the NF-kappaB subunit p65 was determined using a DNA binding assay kit. A millimolar level of TauCl was formed in the inflamed tissue. TauCl inhibited tumor necrosis factor (TNF)-dependent NF-kappaB activation by modifying thiol(s) on p65 and blocking DNA binding. In addition, 5-ASA inhibited phosphorylation of p65 at serine 536, which is critical for transcriptional activity of NF-kappaB. Furthermore, combined TauCl/5-ASA treatment additively inhibited TNF-dependent NF-kappaB activation. Together, our data suggest that the colon-specific carrier taurine contributes to the clinical effect of the prodrug by potentiating the inhibitory effect of the active ingredient 5-ASA on a major proinflammatory signal, TNF-dependent NF-kappaB activation in the inflamed large intestine.
authors.affiliation: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Korea 609-735.
authors.forename: Heejung
authors.initials: H
authors.lastname: Kim
authors.forename: Hyunchu
authors.initials: H
authors.lastname: Jeon
authors.forename: Hyesik
authors.initials: H
authors.lastname: Kong
authors.forename: Youngwook
authors.initials: Y
authors.lastname: Yang
authors.forename: Boim
authors.initials: B
authors.lastname: Choi
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019804:Mesalamine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D012694:Serine / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013654:Taurine; D012694:Serine; D019804:Mesalamine; C043410:N-chlorotaurine