PREDNISOLONE STIMULATES HEPATIC GLUTATHIONE SYNTHESIS IN MICE - PROTECTION BY PREDNISOLONE AGAINST ACETAMINOPHEN HEPATOTOXICITY INVIVO

Mediators of inflammation modulate the extent of hepatocellular necros is following the administration of hepatotoxins. Since corticosteroids interfere with the generation of some of these mediators they might t hus protect against the hepatotoxicity of drugs such as acetaminophen. To test this hypothesis mice were pretreated with two doses of predni solone (10 and 20 mg/kg i.p., 17 and 2 h, respectively) prior to a hep atotoxic dose of 375 mg/kg acetaminophen and the metabolism and toxici ty of acetaminophen were assessed. Twenty-four hours after acetaminoph en the activity of ALT in plasma (737 vs. 6775 U/l) and the extent of hepatocellular necrosis (4 vs. 45% necrotic hepatocytes) were signific antly lower in prednisolone-pretreated mice. Prednisolone pretreatment resulted in decreased covalent binding of the toxic metabolite in viv o and an increased urinary excretion of glutathione-derived conjugates of acetaminophen, indicating an enhanced detoxification of the reacti ve metabolite by glutathione. Nevertheless, hepatic glutathione was le ss depleted by acetaminophen in the prednisolone group, indicating an increased capacity to resynthesize glutathione. This was confirmed in experiments with diethyl maleate which depletes hepatic glutathione wi thout causing cell injury. Following the administration of diethyl mal eate to fed and fasted mice, hepatic glutathione was depleted to the s ame extent after 45 min, but was significantly higher after 2.5 h in p rednisolone-pretreated mice. The present results indicate that prednis olone increases the capacity to replete depleted hepatic glutathione s tores in mice.