Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat

Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glu curonidation and sulfatation and a small fraction is oxidized by cytochrome s P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GS H, anal then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation anal sulfatation pathways a re saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in r at in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rate s 24 h after APAP overdose (2 X 500 mg/kg) were 63% (control), 38% (NAC), 0 % (STP), and 4% (STP + NAG). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP an d NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5h) for A PAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercaptu rate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats. (C) 2001 Academi c Press.