| Budget Amount *help |
¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1993: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1992: ¥800,000 (Direct Cost: ¥800,000)
|
|---|
| Research Abstract |
I invistigated the effects of papaverine, glucagon and DBcAMP on bile acid excretion into bile and biliary excretion of horseradish peroxidase(HRP), a conventional marker of the transcytotic vesicle trasport, using a single-pass isolated perfused rat liver model. Papaverine reduced biliary excretion of HRP and significantly inhibited biliary excretion of bile acids in the presence of lowdose taurochenodeoxcholic acid(TCDCA)and high-dose taurocholic acid. In contrast, glucagon and DBcAMP, which enhanced bikiary excretion of HPRP, increased bile acids excretion into bile.
Furthermore, I examined the cytotoxicity of TCDCA in primary cultured rat hepatocytes focusing on change in intracellular bile acid content. The data revealed that hepatotoxicity by TCDCA is dependent on its inrtacellular content on TCDCA-induced cytotoxicity. The secondary messenger cyclic AMP plays an important role in regulating billariy excretory function by stemukating the transcytotic vesicle transport system, while papaverine exerts an inhibitory effect in this system. I therefore investigated their effects on bile acid-induced cytotoxicity and intrahepatocytic content of bile acidin primary cultured rat hepatocytes. DBcAMP clearly reduced the cytotoxicity of TCDCA and its content in the hepatocytes. Papaverine increased the cytotoxicity of TCDCA by suppressing its efflux from hepatocytes and by increasing intracellular content.
These findings fidicate that bile acid-induced hepatotoxicity is actually dependent on intracellular content and that a vesicular pathway is involved in intrahepatocytic transport of more hydrophobic bile acids such as TCDCA.
|
