The insulin-like growth factor-I receptor (IGFR) is involved in estradiol-17beta-Dglucuronide (E17G) induced cholestasis in isolated perfused rat liver (IPRL).

BAROSSO, IR; ANDERMATTEN, ROMINA; CIRIACI, NADIA; MISZCZUK, GS; MAIDAGAN, PAULA; SANCHEZ POZZI, EJ

Mar del Plata

Congreso; Reunión Anual de SAIC-SAI 2016; 2016

SAIC-SAI

E17G internalizes canalicular transporters such as Mrp2 and Bsep (model of intrahepatic cholestasis of pregnancy), by activating two different pathways each one involving an estrogen receptor: ERα or GPR30. GPR30 activates adenylyl cyclase-PKA and PI3K/Akt, being the latter pathway responsible for keeping transporters in a subapical space, restraining reinsertion. Previous works demonstrated that IGFR participates downstream of GPR30 in culture of rat hepatocyte couplets, so the role of IGFR was evaluated in a physiological model as IPRL. Livers were perfused in situ via the portal vein in a non-recirculatingsingle-pass design. Taurocholate (5μM, Bsep sustrate) and 1-chloro-2,4-dinitrobenzene (0.5 μM, precursor of DNP-glutathione, Mrp2 substrate) were added to the perfusion medium to estimate Bsep and Mrp2 activities. After a 20-min. equilibration period, Tyrphostin AG1024 (AG,100 nM), IGFR inhibitor, or its solvent (DMSO, 370μl/L) was added to the reservoir. Ten minutes later, a 5 min basal bile sample was collected, followed by administration of E17G (3 μmol/liver, intraportal) or its solvent (DMSO/10% BSA in saline), and bile collected at 5-min intervals for 40 min.: bile flow was determined gravimetrically (only if initial bile flow was greater than 15 μL/ min/kg). Biliary excretion of DNP-glutathione was determined by HPLC and that of BS by 3a-hydroxysteroid method.AG did not prevent the drop induced by E17G (40 %) in the three parameters measured, but accelerated the recovery of both bile flow (significant from 15 min of E17G administration on) and biliary excretion of DNP-glutathione and BS (significant from 25 min of E17G administration on). (p