MRP2 mediated defense against oxidative stress in liver

肝脏的氧化应激有时伴有胆汁淤积。我们描述了在乙酸（EA）诱导的大鼠肝脏急性氧化应激下，多药耐药相关蛋白2/ atp结合盒转运蛋白家族2 （Mrp2/Abcc2）的内化，这是一种胆道转运蛋白，参与不依赖胆盐的胆汁流动。然而，信号通路和调控分子仍有待研究。在这项研究中，我们利用分离的大鼠肝细胞偶联（IRCHs）研究了ea诱导Mrp2内化的机制。Mrp2指数，定义为IRCHs中Mrp2阳性小管膜染色与细胞核数量的比值，在EA处理后显著降低。通过使用该系统，我们发现EA可以降低GSH，Ca^<2+>升高，NO产生，nPKC激活，最终导致选择性Mrp2内化。除此之外，我们还证明了一种非甾体抗炎药萘普生诱导的氧化应激也会导致胆汁淤积，这是由于GSH排泄到胆汁中的减少引起的。由于已知GSH本身是Mrp2的良好底物，我们认为Mrp2内化也导致萘普生诱导的胆汁淤积。最后，这些新发现可能有助于解决药物性肝炎和衰老引起的胆汁淤积的机制。

Oxidative stress in the liver is sometimes accompanied by cholestasis. We have described the internalization of multidrug resistance-associated protein 2/ ATP-binding cassette transporter family 2 (Mrp2/Abcc2), a biliary transporter involved in bile-salt-independent bile flow, under ethacrynic acid (EA)-induced acute oxidative stress in rat liver. However, the signaling pathway and regulatory molecules have been remained to be investigated. In this research, we investigated the mechanism of EA-induced Mrp2 internalization using isolated rat hepatocyte couplets (IRCHs). The Mrp2-index, defined as the ratio of Mrp2 positive canalicular membrane staining in IRCHs per number of cell nuclei, was significantly reduced by treatment with EA. By using this system, we have found EA produced a reduction in GSH,Ca^<2+> elevation, NO production, nPKC activation in a sequential manner, finally leading to selective Mrp2 internalization. In addition to this, we demonstrated one of the non-steroidal anti-inflammatory drugs, Naproxen induced oxidative stress also leads to cholestasis caused by decrease excretion of GSH into bile. As GSH itself is known to be a good substrate of Mrp2, we thought Mrp2 internalization also caused Naproxen-induced cholestasis. Finally, these new findings might be able to solve the mechanism of cholestasis caused by drug-induced hepatitis and aging.