Mechanism of liver mitochondrial dysfunction associated with bile duct obstruction.

To elucidate the mechanism of liver mitochondrial dysfunction induced by obstructive jaundice, the following experiments were performed. In vivo study: Using Wistar male rats, bile ducts were ligated, and serum levels of total bilirubin (T-Bil), GOT, GPT, mitochondrial GOT (mGOT) and total bile acids (TBA) were measured at 3 and 7 days after the ligation. Then, the liver was isolated to determine mitochondrial functions and to measure the content of fatty acids in mitochondrial phospholipids by high performance liquid chromatography. The levels of T-Bil, GOT, GPT, mGOT and TBA were elevated by the bile duct ligation. Mitochondrial functions were deteriorated, and contents of arachidonic acid, palmitic acid and stearic acid in mitochondrial phospholipids decreased. Pretreatment with coenzyme Q10 (E-0216, CoQ10), an antidetergent agent, prevented not only the development of mitochondrial dysfunction and the decrease in mitochondrial phospholipids but also the elevation of GOT, GPT, and mGOT although CoQ10 did not prevent the elevation of T-Bil and TBA levels. In vitro study: Using intact rat liver mitochondria, the effect of taurocholic acid (TCA), one of the physiological bile salts, on the mitochondrial function and on mitochondrial phospholipids was examined. Incubation of mitochondria with TCA induced a dose-dependent deterioration of mitochondrial function and the increase in the content of solubilized phospholipids. The protective effect of CoQ10 was also observed in the in vitro study. These results indicate that degradation of mitochondrial phospholipids by bile acids is responsible for the early phase of liver dysfunction induced by obstructive jaundice.