Oral N-acetylcysteine has a deleterious effect in acute iron intoxication in rats.

Acute iron intoxication is associated with depletion of reduced glutathione in hepatocytes and changes in the glutathione system enzymes. We hypothesized that treatment with N-acetylcysteine (NAC), a glutathione reducing agent and an antioxidant, would reduce mortality in acute iron intoxication. We used a rat model to test this hypothesis. Male rats were assigned to 4 groups. Group 1 received 400 mg/kg elemental iron by oral gavage, group 2 received the same dose of iron followed by NAC, group 3 received NAC only, whereas group 4 received distilled water. Iron and liver transaminases in the blood, and glutathione system enzymes in the liver and erythrocytes were measured. Mortality in group 2 was significantly higher after 2, 6, and 24 hours compared with group 1 (P < .001). No deaths were observed in groups 3 and 4. Serum iron levels were significantly higher in group 2 rats compared to group 1 rats (P < .001). Hepatic and erythrocyte glutathione system enzymes were significantly lower among rats in group 2 compared to rats in group 1. The administration of NAC probably increased the absorption of iron through the gastrointestinal tract, causing higher serum iron levels with significant hepatic damage. These results indicate that in a rat model of acute iron intoxication, orally administered NAC may increase mortality.

Depletion of glutathione system enzymes of the liver and erythrocytes in a rat model of acute iron poisoning.

ABSTRACT The proposed mechanism of iron-induced hepatotoxicity is free radical formation. It was hypothesized that the glutathione system of the liver and erythrocytes will be affected by acute iron poisoning. Male Wistar rats, 6-8 weeks of age, were assigned to one of three groups. Group I received distilled water, group II received 400 mg/kg elemental iron, and group III received 750 mg/kg elemental iron. All groups were gavage fed. Iron concentration, glutathione, and glutathione system enzymes were then measured in the liver and erythrocytes. The hepatic level of reduced glutathione (GSH) was significantly lower in groups II (3.1 +/- 4.6 mumol/mg protein) and III (4.7 +/- 4.6 mumol/mg protein) in comparison with group I (11.5 +/- 6.2 mumol/mg protein) (p < 0.001). Hepatic levels of glutathione S-transferase (GST) were higher and glutathione peroxidase (GPX) levels were lower in group III compared to groups II and I (p < 0.001 and p < 0.001). Compared to group I, glutathione reductase (GR) was lower in groups II and III (p < 0.001). There was no correlation between GSH, oxidized glutathione (GSSG), GST, GR, and GPX levels in the erythrocytes and in the liver (p = 0.41, p = 0.48, p = 0.49, p = 0.53, p = 01.4, and p = 0.84, respectively). In conclusion, acute iron intoxication in rats is associated with depletion of reduced glutathione in the liver.

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 degrees 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 micromol gHb(-1), 95% confidence interval (CI) 2.10-4.72, and 2.15 micromol gHb(-1), 95% CI 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.

A prospective study of multiple supratherapeutic acetaminophen doses in febrile children.

Repeated doses of acetaminophen given for therapeutic reasons have been reported to cause hepatotoxicity in adults and children. We studied the effect of repeated acetaminophen (APAP) overdoses administered for therapeutic purposes in a prospective cohort of children. Forty-four children, aged 2 mo to 10 y were referred with a fever of >38.5 C for more than 48 h, and received >60 mg APAP/kg/d. In each patient AST, ALT and APAP blood levels were measured. The mean total daily dose of APAP was 92+/-26 (63-171) mg/kg. There was a weak, but significant, negative correlation between age and daily dose of APAP where younger children received higher doses of APAP. In 4 children (9.1%) an elevation of AST and ALT was found. Three of the 4 patients with elevated liver enzymes had received >90 mg APAP/kg/day; APAP blood levels ranged from 0 to 23 mg/mL. No correlation was found between the time since last APAP dose and the serum drug level. Ill children receiving repeated supratherapeutic doses of acetaminophen may show abnormalities in liver function. However, severe liver injury was rare.