RT Journal Article
SR Electronic
T1 A Molecular Mechanism for the Anti-Inflammatory Effect of Taurine-Conjugated 5-Aminosalicylic Acid in Inflamed Colon
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1405
OP 1412
DO 10.1124/mol.105.020578
VO 69
IS 4
A1 Kim, Heejung
A1 Jeon, Hyunchu
A1 Kong, Hyesik
A1 Yang, Youngwook
A1 Choi, Boim
A1 Kim, Young Mi
A1 Neckers, Len
A1 Jung, Yunjin
YR 2006
UL http://molpharm.aspetjournals.org/content/69/4/1405.abstract
AB 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-κB (NF-κB) activity was accessed using an NF-κB-dependent luciferase reporter gene. Protein levels were monitored by Western blotting. DNA binding activity of the NF-κB 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-κB 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-κB. Furthermore, combined TauCl/5-ASA treatment additively inhibited TNF-dependent NF-κB 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-κB activation in the inflamed large intestine.