Endotoxin protects against chlorpromazine-induced cholestasis in the isolated perfused rat liver

Induction of endotoxin tolerance or acute chlorpromazine treatment caused a decrease in bile and perfusate flow in the isolated perfused rat liver. The primary effects of each appeared to be on the bile acid-independent fraction of bile. Both the induction of endotoxin tolerance and the in vitro treatment of the perfused rat liver with endotoxin partially blocked the adverse effects of chlorpromazine on bile formation and perfusate flow. Although the "protective" effects of the in vitro endotoxin treatment were dose-dependent, the protection afforded by endotoxin tolerance was greater. Preincubation of isolated hepatocytes with endotoxin, before the addition of chlorpromazine, caused dose-dependent reductions in the chlorpromazine-induced release of aspartate transaminase. However, neither the incubation of endotoxin with chlorpromazine, before addition of membranes isolated from control rats, nor isolation of membranes from endotoxin-tolerant rats affected the inhibitory effects of chlorpromazine on sodium, potassium-, or magnesium-activated adenosine triphosphatase. If endotoxin exerts its protective effects at the membrane level, these data suggest that endotoxin is able to protect the intact, but not the isolated, hepatocyte membrane or that inhibition of adenosine triphosphatases by chlorpromazine is not important in the adverse effects of chlorpromazine on the perfused rat liver and isolated rat hepatocytes.