Related Experiment Video
Updated: Jun 10, 2026
Visualization of Vascular Ca2+ Signaling Triggered by Paracrine Derived ROS
Published on: December 21, 2011
Oxidative stress is a triggering factor for LPS-induced Mrp2 internalization in the cryopreserved rat and human liver
Shuichi Sekine1, Kentaro Yano, Junjiro Saeki
1Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Abstract:
Cholestasis develops during inflammation and is characterized as occurring under oxidative stress. We have described the internalization of multidrug resistance-associated protein 2 (Mrp2), a biliary transporter involved in bile-salt-independent bile flow, under ethacrynic acid or lipopolysaccharide (LPS)-induced acute oxidative stress in rat liver. However, it remains unclear whether canalicular Mrp2 internalization is observed in human liver under conditions of acute oxidative stress. In this study, we examined the effect of dimerumic acid (DMA), an antioxidant and found in traditional Chinese medicine, on endotoxin-induced Mrp2 internalization in rat and human liver slices. At 1.5h following LPS treatment (100microg/mL), canalicular Mrp2 localization was disrupted without changing the expression of Mrp2 protein or the integrity of filamentous actin in the rat and human liver slices. Pretreatment with DMA (10microM) counteracted LPS-induced subcellular distribution of Mrp2. Our data clearly indicated that LPS-induced short-term rapid retrieval of Mrp2 from the canalicular surface resulted from LPS-induced oxidative stress in rat and human liver slices.
Insights
Dimerumic acid (DMA) prevents endotoxin-induced oxidative stress, which disrupts multidrug resistance-associated protein 2 (Mrp2) localization in rat and human liver. This antioxidant effect protects bile-salt-independent bile flow.
Area of Science:
- Hepatology
- Biochemistry
- Toxicology
Background:
- Cholestasis, linked to inflammation and oxidative stress, involves impaired bile flow.
- Multidrug resistance-associated protein 2 (Mrp2) is a key biliary transporter for bile-salt-independent bile flow.
- LPS-induced oxidative stress causes Mrp2 internalization in rat liver, but its effect in human liver is unclear.
Purpose of the Study:
- To investigate the effect of dimerumic acid (DMA), an antioxidant, on endotoxin-induced Mrp2 internalization in rat and human liver slices.
- To determine if LPS-induced Mrp2 internalization occurs in human liver under acute oxidative stress.
Main Methods:
- Treatment of rat and human liver slices with lipopolysaccharide (LPS) and dimerumic acid (DMA).
- Analysis of canalicular Mrp2 localization and protein expression.
- Assessment of filamentous actin integrity.
Main Results:
- LPS treatment disrupted canalicular Mrp2 localization in both rat and human liver slices within 1.5 hours.
- Mrp2 protein expression and filamentous actin integrity remained unchanged.
- DMA pretreatment effectively counteracted the LPS-induced Mrp2 redistribution.
Conclusions:
- Endotoxin-induced oxidative stress causes rapid, short-term Mrp2 internalization from the canalicular surface in both rat and human liver.
- DMA exhibits protective effects against LPS-induced Mrp2 internalization, suggesting its therapeutic potential in cholestasis associated with oxidative stress.
