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1. The effect on hepatic glutathione was studied in rats pretreated orally with various dosages of paracetamol (acetaminophen) for varying time intervals. 2. Paracetamol caused a dose-dependent depletion of hepatic glutathione, the maximum depletion occurring 3 h after acute dosing, the levels returning to normal by 12 h after low doses (0-1 or 0-25 g/kg, p.o.) and by 72 h after the highest doses (1 g/kg, p.o.). 3. Before returning to normal, the liver glutathione levels became significantly greater than the control values (35-40%) at 24 and 48 h in 0-5 and 1 g/kg paracetamol-treated rats, respectively, suggesting thereby a 'glutathione rebound action' of paracetamol-pretreatment. 4. In contrast with the acutely treated rats, the liver glutathione content remained unchanged when 0-5 g/kg paracetamol was administered twice daily for 7 consecutive days. 5. Fasting caused a significant reduction in hepatic glutathione, the glutathione stores were replenished within 6 h after feeding. 6. The results suggest that the hepatic glutathione levels are reversibly depleted by single large doses of paracetamol, while the glutathione depletory effect appears to decrease after the repeated administration of this hepatotoxic agent.

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