Role of the hepatic function in the development of the pyrogenic toleranceto muramyl dipeptide

We have demonstrated that the hepatic function may have an important role i n the development of tolerance to the pyrogenic effect induced by endotoxin . To further investigate if the role of the hepatic function in the develop ment of tolerance also extends to that induced by other pyrogenic stimuli, we investigated the effect of galactosamine, a specific inhibitor of the he patic protein synthesis, on the development of tolerance to the pyrogenic e ffect induced by muramyl dipeptide (MDP) in rats. Pyrogenic tolerance was o bserved after the second intravenous or intraperitoneal injection of MDP (5 00 mug/kg), 24 h after the first injection, similar to what was observed wi th endotoxin. Pyrogenic tolerance was abolished when galactosamine (300 mg/ kg ip) was injected simultaneously with MDP (500 mug/kg iv) on the first da y. When uridine (600 mg/kg ip) was administered simultaneously with galacto samine (300 mg/kg ip) and the first injection of MDP (500 mug/kg ip), pyrog enic tolerance was again observed after the second injection of the peptido glycan. In conclusion, the hepatic function may not be important only for t he development of tolerance to endotoxin, but also to a totally different p yrogenic stimulus such as MDP.