The hepatoprotective effect of N-acetylcysteine in acetaminophen intoxication is due to early glutathione replenishment via stimulation of anaplerotic mechanisms

T. Chan, V-A. Raymond, M. Bilodeau, D. Leibfritz, C. Zwingmann Centre de Recherche, Hospital Saint-Luc, Montreal, Quebec, Canada, Department of Organic Chemistry, University of Bremen, Bremen, Bremen, Germany Introduction. Acetaminophen (AAP) is converted by the cytochrome P450 pathway to a toxic intermediate, N-acetyl-p-benzoquinone-imine (NAPQI), which is usually completely detoxified through combination with glutathione (GSH) [1]. In the event of an overdose, the P450 pathway is accelerated, and glutathione levels begin to deplete [2-4]. Once the pathway consumes approximately 70% of the available glutathione, NAPQI is no longer detoxified and can bind to slufhydryl groups, leading eventually lead to cell necrosis [5]. N-acetylcysteine (NAC), the most widely used antidote in acetaminophen intoxication, is believed to act by regenera-ting glutathione (GSH) stores [3]. NAC is a delivery form of L-cysteine, which serves as a major precursor and rate-limiting amino acid to the antioxidant GSH. BUT: GSH synthesis depends not only on the availability of cysteine, but also on the provision of glutamate, which is regulated by Krebs cycle associated metabolic pathways (Fig. 1).