TAUROURSODEOXYCHOLATE PREVENTS ESTRADIOL 17beta-D-GLUCURONIDE-MEDIATED CHOLESTASIS BY INHIBITING THE PHOSPHORYLATIVE ACTIVATION OF PRO-CHOLESTATIC PROTEIN KINASES, INDEPENDENTLY OF PROTEIN PHOSPHATASES

MAIDAGáN, PAULA M.; BOAGLIO, ANDREA C; RAZORI, M. VALERIA; CIRIACI, NADIA; MISZCZUK, GISEL SABRINA; CROCENZI, FERNANDO A.; ROMA, MARCELO G

Mar del Plata

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2016

We have previously shown (Hepatology 52:1465-76, 2010) thatestradiol 17b-D-glucuronide (E217G), etiologic agent of pregnancy-induced cholestasis, alters function and location of both Mrp2 andBsep, two key canalicular transporters involved in bile formation, byenhancing phosphorylative activation of ?classical? protein kinaseC (PKCc) and phosphatidylinositol 3 kinase (PI3K)/Akt-dependentsignaling pathways. Pregnancy-induced cholestasis is treated withursodeoxycholate, but its therapeutic mechanisms are unknown.We therefore evaluated whether its active metabolite, tauroursodeoxycholate(TUDC), prevents E217G-induced canalicular secretoryfailure by inhibiting the phosphorylative activation of PKCc and PI3K/Akt, and whether protein phosphatases (PPs) are involved. For thispurpose, we studied by Western Blot, in isolated rat hepatocytes, theeffect of TUDC on activation of PKCc (% of membrane translocation)and Akt (% of phosphorylated form). Pretreatment with TUDC (100ìM), followed by exposure to E217G (100 ìM), prevented activationof PKCc (-34±4%) and Akt (-37±2%); p