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ORIGINAL RESEARCH ARTICLE

Double Null of Selenium–Glutathione Peroxidase-1 and Copper, Zinc–Superoxide Dismutase Enhances Resistance of Mouse Primary Hepatocytes to Acetaminophen Toxicity

Department of Animal Science, Cornell University, Ithaca, NY 14853

To whom requests for reprints should be addressed at ¹ Cornell University, 252 Morrison Hall, Ithaca, NY 14853. E-mail: XL20{at}cornell.edu

This study was conducted to determine the impact of knockout of selenium (Se)-dependent glutathione peroxidase-1 (GPX1^–/–) or double knockout of GPX1 and copper, zinc (Cu,Zn)–super-oxide dismutase (SOD1) on cell death induced by acetaminophen (APAP) and its major toxic metabolite N-acetyl-P-benzoquinoneimine (NAPQI). Primary hepatocytes were isolated from GPX1^–/–, double knockout of GPX1 and SOD1 (DKO), and their wild-type (WT) mice and were treated with 5 mM APAP or 100 µM NAPQI for 0, 6, and 12 hrs. Compared with the WT cells, the GPX1^–/– and DKO hepatocytes were more resistant (P < 0.05) to the APAP-induced cell death but less resistant to the NAPQI-induced cell death. The APAP-mediated glutathione (GSH) depletion was greater (P < 0.05) at 6 hrs in the WT cells than in the GPX1^–/– and DKO cells, whereas there was no genotype effect on the NAPQI-mediated GSH depletion. The DKO cells had lower (P < 0.05) microsomal cytochrome P450 2E1 activities, but higher (P < 0.05) glutathione reductase and thioredoxin reductase activities than the WT cells at 0 hrs, and they responded differently to the APAP and NAPQI treatments. Glutathione-S-transferase activity was not affected by genotypes or treatments. Neither APAP nor NAPQI induced nitric oxide production or protein nitration in cells of any genotype. However, the GPX1^–/– and DKO cells were more resistant to peroxynitrite-mediated protein nitration than were the WT cells. In conclusion, double null of GPX1 and SOD1 enhanced the resistance of mouse primary hepatocytes to APAP toxicity by affecting events prior to or at NAPQI formation. While the double knockout attenuated the peroxynitrite-mediated protein nitration in hepatocytes, no protein nitration was detected in these cells treated with APAP or NAPQI.

Key Words: acetaminophen • cell death • protein nitration • peroxynitrite • glutathione peroxidase • superoxide dismutase