Ebselen and diphenyl diselenide change biochemical hepatic responses to overdosage with paracetamol

The toxicity of paracetamol is largely related to its conversion to the reactive intermediate alkylating metabolite N-acetyl-para-benzo-quinoneimine (NAPQI). δ-Aminolevulinate dehydratase (δ-ALA-D) is a sulfhydril containing enzyme which is extremely sensitive to oxidizing and alkylating agents. In the present study, we examined whether acute treatment with paracetamol changes δ-ALA-D activity. The influence of two organochalcogenides with glutathione peroxidase-like activity, diphenyl diselenide [(PhSe)(2)] and ebselen was also assessed as potential protecting agents against paracetamol toxicity. Paracetamol (1200mg/kg for three days 4h after the injection of DMSO, diphenyl diselenide (100μmol/kg) or ebselen (100μmol/kg) caused an inhibition of about 40% (P < 0.01) in hepatic δ-ALA-D. Ebselen restored enzyme activity to control values. Non-protein-SH and ascorbic acid were diminished to 50% of control value by paracetamol, independent of chalcogenides treatment (all P values <0.05). In view of the fact that paracetamol caused a massive reduction in non-protein-SH and ascorbic acid, we realize that the protective effect of ebselen on δ-ALA-D activity is mediated by its thiol peroxidase-like activity or by a direct interaction with NAPQI and other reactive species formed during paracetamol metabolism.