Effect of trifluoperazine on toxicity, HIF-1¦Á induction and hepatocyte regeneration in acetaminophen toxicity in mice

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• 作者：Shubhra Chaudhuri ; S ; ra S. McCullough ; Leah Hennings ; Aliza T. Brown ; Shun-Hwa Li ; Pippa M. Simpson ; Jack A. Hinson ; Laura P. James
• 关键词：APAP ; acetaminophen ; ALT ; alanine aminotransferase ; cPLA2 ; cytosolic phospholipase A2 ; (CYC) ; cyclosporine A ; GSH ; glutathione ; HIF-1¦Á ; hypoxia inducible factor-1¦Á ; MPT ; mitochondrial permeability transition ; PCNA ; proliferating cell nuclear antigen ; PG
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2012
• 出版时间：15 October, 2012
• 年：2012
• 卷：264
• 期：2
• 页码：192-201
• 全文大小：1673 K

文摘

Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1¦Á) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1¦Á induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10 mg/kg, oral gavage) prior to APAP (200 mg/kg IP) and at 7 and 36 h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8 h, compared to the APAP mice. At 24 and 48 h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1¦Á induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A₂, and cytosolic and secretory PLA₂ activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E₂ expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1¦Á induction in APAP treated mice. TFP also reduced PGE₂ expression and hepatocyte regeneration, likely through a mechanism involving PLA₂.