2002 Fiscal Year Final Research Report Summary
Evaluation of drug-induced hepatotoxicity by chemiluminescence and the role of MRP2 in the hepatotoxicity
| Project/Area Number |
13470476
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Physical pharmacy
|
|---|
| Research Institution | Chiba University |
|---|
Principal Investigator |
HORIE Toshiharu Chiba University, Graduate School, Professor, 大学院・薬学研究院, 教授 (90120154)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ITO Kousei Chiba University, Graduate School Research assistant, of Pharmaceutical Sciences, professor, 大学院・薬学研究院, 助手 (30323405)
MASUBUCHI Yasuhiro Chiba University, Graduate School, Associate professor, of Pharmaceutical Sciences, 大学院・薬学研究院, 助教授 (10209455)
|
|---|
| Project Period (FY) |
2001 – 2002
|
| Keywords | chemiluminescence / glutathione / oxidative stress / MRP2 / 4-hydroxynonenal / reactive oxygens / hepatotoxicity / hepatocyte |
|---|
| Research Abstract |
The oxidative stress is related to various diseases and drug-induced side effects. In this study, the oxidative stress caused by the drug metabolism in liver was evaluated by ultraweak chemiluminescence. Glutathione (GSH) is excreted through multidrug resistance-associated protein 2 (MKP2), suggesting the involvement of MRP2 in the oxidative stress. Therefore, the present study investigated the role of MRP2 under the oxidative stress, using in vitro, in situ and in vivo experimental systems.
Lipid peroxidation was shown to occur by the oxidative metabolism of ethacrynic acid (EA) in liver. This indicated that the EA-induced oxidative stress was caused not only by the decrease of intracellular GSH induced by the formation of EA'SG conjugate but also by the oxidative metabolism of EA. Salicylic acid and chlorpropamide were found to induce the oxidative stress by their oxidative metabolism, since the ultraweak chemiluminescence was detected during their oxidative metabolism.
4-Hydroxvnonena
… More
l (HNE) is a toxic product of lipid peroxidation. HNE-SG is a major metabolite of HNK The transport of HNE-SG in MEP2HTansfected cells and MRP2-defitient animals (EHKR) was investigated in order to clarify the contribution of MRP2 in its biliary excretion. It was shown that MRP2 played an important role in the biliary excretion of HNE-SG. We further investigated whether the HNE-induced cytotoxicity was reduced by MRP2 using MRP2-iaansfected cells, interestingly, the transfection of MRP2 enhanced the HNE-induced cytotoxicity This may possibly be due to the decrease of intracellular GSH provoked by the MKP2-mediated excretion of GSH and HNE-SG. Further, the cytotoxicity mediated by MRP2 under the oxidative stress was investigated using the in situ liver perfusion of EA. It was shown that the EA-induced hepatotoxicity and the occurrence of lipid peroxidation were markedly reduced in EHBR, compared with those of normal rats. Thus, the oxidative stress-induced cytotoxicity seems to be enhanced by MRP2. Less
|
