Paracetamol metabolism and toxicity in isolated hepatocytes from rat and mouse

Hepatocytes isolated from mouse and rat catalyzed the formation of glucuronide, sulphate, glutathione and cysteine conjugates of paracetamol. These metabolites were separated by high pressure liquid chromatography. 1. Sulphation had higher affinity for paracetamol than glucuronidation in hepatocytes from both mouse and rat, whereas glucuronidation had higher capacity. The maximal rate of glucuronidation was similar in hepatocytes from both species, the rate of sulphation was, however, several-fold less in hepatocytes from mouse. 2. Formation of the glutathione conjugate was directly correlated with loss of intracellular glutathione (GSH). The rate of glutathione conjugate formation increased about three times in rat hepatocytes after phenobarbital treatment. This induced rate was, however, only half of that in hepatocytes from control mouse. In both species the reaction was saturated only at very high paracetamol concentrations. The rate of formation of the cysteine conjugate was very low compared to the other reactions. 3. Only hepatocytes isolated from mouse lost integrity, measured as increased permeability of the cell membranes, upon incubation in the presence of paracetamol.