Induction of the nuclear factor HIF-1α in acetaminophen toxicity:: Evidence for oxidative stress
Induction of the nuclear factor HIF-1α in acetaminophen toxicity:: Evidence for oxidative stress
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DOI：
10.1016/j.bbrc.2006.02.143
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发表时间：
2006-04-28
影响因子：
3.1
通讯作者：
Hinson, JA
中科院分区：
文献类型：
--
作者：
James, LP;Donahower, B;Hinson, JA
缺氧诱导因子（HIF）控制着参与血管生成、红细胞生成、糖酵解和细胞存活的基因的转录。HIF-1 α水平是HIF活性的关键决定因素。用毒性剂量的APAP （300 mg/kg IP）处理小鼠，并在1、2、4、8和12小时处死，观察小鼠肝脏中HIF-1 α的诱导情况。HIF-1 α在1-12小时诱导，诱导发生在毒性发生之前。用n -乙酰半胱氨酸（1200mg /kg IP）预处理小鼠可防止毒性和HIF-1 α诱导。在进一步的研究中，肝细胞悬液与APAP （1mm）在氧气环境中孵育。在毒性发生前1小时诱导HIF-1 α。环孢素A （10 μ M）是线粒体通透性转变、氧化应激和毒性的抑制剂，可阻止HIF-1 α的诱导。因此，HIF-1 α在APAP中毒之前被诱导，并可在非缺氧条件下发生。这些数据表明氧化应激在诱导HIF-1 α在APAP毒性中的作用。(c) 2006爱思唯尔公司版权所有。
Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1 alpha levels are a critical determinant of HIF activity. The induction of HIF-1 alpha was examined in the livers of mice treated with a toxic dose of APAP (300 mg/kg IP) and sacrificed at 1, 2, 4, 8, and 12 h. HIF-1 alpha was induced at 1-12 h and induction occurred prior to the onset of toxicity. Pre-treatment of mice with N-acetylcysteine (1200 mg/kg IP) prevented toxicity and HIF-1 alpha induction. In further studies, hepatocyte suspensions were incubated with APAP (1 mM) in the presence of an oxygen atmosphere. HIF-1 alpha was induced at 1 h, prior to the onset of toxicity. Inclusion of cyclosporine A (10 mu M), an inhibitor of mitochondrial permeability transition, oxidative stress, and toxicity, prevented the induction of HIF-1 alpha. Thus, HIF-1 alpha is induced before APAP toxicity and can occur under non-hypoxic conditions. The data suggest a role for oxidative stress in the induction of HIF-1 alpha in APAP toxicity. (c) 2006 Elsevier Inc. All rights reserved.