Hepatic glutathione and lipid peroxidation in rats treated with theophylline. Effect of dose and combination with caffeine and acetaminophen.

As theophylline, caffeine and acetaminophen (APAP) are commonly found in combination in prescription and non-prescription drugs, the present study was designed to evaluate changes of hepatic glutathione (GSH) and lipid peroxidation in rats treated concurrently with these widely used drugs. In rats treated with different doses of theophylline, a dose-related depletion of hepatic GSH was observed (r = -0.88, P < 0.001). After a dose of 100 mg/kg of caffeine given alone and in combination with 50 mg/kg of theophylline, hepatic GSH levels were decreased by 22.5% (P > 0.05) and 35.5% (P < 0.01) of the control value, respectively. Also, the challenge with 500 mg/kg of APAP significantly depleted hepatic GSH in rats pretreated with either saline or the combination of both theophylline and caffeine (50 and 100 mg/kg, respectively), P < 0.001. In the latter group, hepatic GSH levels were approximately 47% of the corresponding values in rats that received APAP (P < 0.02). Such severe depletion of hepatic GSH, in rats that received the three drugs, was associated with a significant rise in the extent of lipid peroxidation (P < 0.05). The other experimental groups treated with one or two drugs did not exhibit similar changes. These results suggest that the concomitant administration of theophylline, caffeine and APAP may enhance the susceptibility of the liver cells to the toxic effect of APAP by severely depleting hepatic GSH with subsequent induction of lipid peroxidation.