Glutathione, glutathione-dependent enzymes and antioxidant status in erythrocytes from children treated with high-dose paracetamol

Aim: To investigate glutathione and antioxidant status changes in erythrocytes from febrile children receiving repeated supratherapeutic paracetamol doses. Methods: Fifty-one children aged 2 months to 10 years participated in the study. Three groups were studied: group 1 (n = 24) included afebrile children who did not receive paracetamol; and groups 2 (n = 13) and 3 (n= 14) included children who had fever above 38.5°C for more than 72 h. Patients in group 2 received paracetamol at a dose of 50 ± 15 (30-75) mg kg^-1 day^-1 and those in group 3 received paracetamol above the recommended therapeutic dose, ie 107 ± 28 (80-180) mg kg^-1 day^-1. A blood sample was taken for the measurement of liver transaminases, gammaglutamil transferase (GGT), reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S-transferase (GST), superoxide dismutase (SOD) and antioxidant status. Results: Aspartate aminotransferase activity in group 3 was higher than in the other groups (P = 0.027). GSH, SOD and antioxidant status were significantly lower in group 3 compared with groups 1 and 2 (mean differences: for GSH 3.41 μmol gHb^-1, 95% confidence interval (CI) 2.10-4.72, and 2.15 μmol gHb^-1, 95% Cl 0.65-3.65, respectively; for SOD 856 U min^-1 gHb^-1, 95% CI 397-1316, and 556 U min^-1 gHb^-1, 95% CI 30-1082, respectively; and for antioxidant status 0.83 mmol l^-1 plasma, 95% CI 0.30-1.36, and 0.63 mmol l^-1 plasma, 95% CI 0.02-1.24, respectively). GR activity was significantly lower in groups 3 and 2 in comparison with group 1 (mean differences 3.44 U min^-1 gHb^-1, 95% CI 0.63-6.25, and 5.64 U min^-1 gHb^-1, 95% CI 2.90-8.38, respectively). Using multiple regression analysis, paracetamol dose was found to be the only independent variable affecting GR, GST and SOD activities (P = 0.007, 0.003 and 0.008, respectively). Conclusions: In febrile children, treatment with repeated supratherapeutic doses of paracetamol is associated with reduced antioxidant status and erythrocyte glutathione concentrations. These significant changes may indicate an increased risk for hepatotoxicity and liver damage.