Efsect ofursodeoxycholic acid on in vivo and in vitro toxic liver injury in rats

Abstract

Benefits of ursodeoxycholic acid (UDCA) in cholestatic disorders have been well documented. However, the therapeutic potential of UDCA in parenchymal liver disease is unclear. We tested UDCA in rat models of hepatotoxicity: (a) in subacute liver injury induced by repetitive CCl4 and dietary ethyl alcohol (ETH) over seven weeks while receiving oral UDCA; and, (b) in liver slides incubated with CCl4, ETH or p-acetaminophen (APAP) when UDCA was added to the incubating solution. Experiment 1: CCl4 combined with ETH reduced the body weights and resulted in 43% mortality. There was a significant rise in serum ALT, alkaline phosphatase, lipoperoxides (LPO) and in hepatic weight, triglycerides, LPO and histological scores of liver injury. Experiment 2: When liver slides were incubated with hepatotoxins there was an increased transfer of AST and LPO from the tissue into the incubate and a reduction in the valine and thymidine incorporation into the liver proteins or DNA. In none of these situations, whether the liver damage was severe or mild, in vivo or in vitro, UDCA did abolish these hepatotoxic effects. In contrast to clinical cholestatic disorders where the reported benefits of UDCA depend on replacement of the accumulated hydrophobic bile acids, these bile acids have a less prominent role in toxic liver injury and UDCA is ineffective.