疾患、薬物による胆管側膜輸送体の局在変動

抄録

ATP-binding cassette (ABC) transporters expressed on the bile canalicular membrane of the hepatocytes are rapidly internalized from and reinserted to the plasma membrane by a variety of stimulus including oxidative stress, osmolarity change, drug treatment and so on. Such re-localization of the transporter molecules sometimes leads to cholestasis or choleresis, although precise intracellular signaling pathway and final molecular determinants involved in the specific transporter internalization is not elucidated. ABCC2/MRP2 and ABCB11/BSEP are both biliary transporters involved in bile flow, by excreting organic anions (glutathione conjugates, glucuronide conjugates, reduced glutathine) and bile salts, respectively, into bile. We are studying the intracellular signaling pathway triggered by GSH depletion and finally leading to Mrp2-specific internalization using isolated rat hepatocytes coulplets as a experimental model. As a result, GSH depletion induced by ethacrynic acid treatment produces nitric oxide (NO) followed by novel protein kinase C (nPKC) activation. Molecular mechanism regulating Mrp2-specific internalization are discussed in relation to canalicular scaffold proteins and other canalicular ABC transporter molecules. [J Physiol Sci. 2006;56 Suppl:S10]