Mechanisms of tauroursodeoxycholate-mediated inhibition of apoptosis

Excerpt

The hydrophilic bile acid ursodeoxycholic acid (UDCA), which in vivo is converted to its taurine conjugate tauroursodeoxycholic acid (TUDC), is a mainstay in the treatment of cholestatic liver disease. TUDC prevents bile acid-induced cholestasis and induces choleresis. Its beneficial effects involve an increased hepatobiliary secretion as well as cytoprotective and antiapoptotic effects. The choleretic effect of TUDC largely depends on a rapid targeting and insertion of intracellularly stored transport ATPases into the canalicular membrane, such as the bile salt export pump (Bsep) and multidrug resistance protein-2 (Mrp2) [1]. It was recently shown that the TUDC-induced signaling involves phosphorylation of the epidermal growth factor receptor (EGFR) at tyrosine 845 and 1173, but not Tyr1045. Tyr845, a known Src kinase target, triggers an activating autophosphorylation at Tyr1173 of the EGFR [2]. Furthermore, c-Src, focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K) and Ras/Raf are activated within minutes by TUDC, which triggers downstream dual activation of extracellular signal-regulated kinases (Erks) and p38 mitogen-activated protein kinase (p38^MAPK) [1‐4]. …