Taurodeoxycholate-induced intestinal injury is modulated by oxidative stress-dependent pre-conditioning like mechanisms

Abstract

Mechanisms by which hydrophobic bile salts cause tissue changes below their critical micellar concentration (CMC, 1–2 mM) and above (4–8 mM) remain poorly understood. In this study, rat colonic mucosa was exposed to different concentrations of taurodeoxycholate (TDC), t-butyl-hydroperoxide ( t-BH) or glutathione ester with or without pre-incubation with 2 mM TDC. Exposure to 2 mM TDC was associated with 10% higher tissue levels of total glutathione (GSH, basal values: 33.7 ± 3.3 nmol/mg prot). With TDC 8 mM, GSH decreased to 16.4 ± 2.3 nmol/mg prot ( P < 0.05), oxidized glutathione (GSSG) increased by 60% ( P < 0.05), glutathione peroxidase (GSH-Px) and reductase activities were threefold increased, protein carbonyls fourfold increased, protein sulfhydrils decreased by 78%, lactate dehydrogenase (LDH) and GSSG release in the incubation medium were sixfold higher. In 2 mM TDC pre-treated tissues, the subsequent incubation with 8 mM TDC induced a lower loss of tissue GSH, and a lower release of LDH and GSSG. Pre-incubation with 2 mM TDC partly protected against t-BH toxicity, while glutathione ester protected against 8 mM TDC toxicity. In conclusion, TDC exposure causes opposite effects depending on CMC: induction of antioxidant protective systems including glutathione system (pre-conditioning effect) was observed with TDC below CMC, oxidative damages pointing to decreased mucosal detoxification potential with above CMC.