James Laura P, Donahower Brian, Burke Angela S, McCullough Sandra, Hinson Jack A
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Biochem Biophys Res Commun. 2006 Apr 28;343(1):171-6. doi: 10.1016/j.bbrc.2006.02.143. Epub 2006 Mar 3.
Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1alpha levels are a critical determinant of HIF activity. The induction of HIF-1alpha was examined in the livers of mice treated with a toxic dose of APAP (300 mg/kg i.p.) and sacrificed at 1, 2, 4, 8, and 12 h. HIF-1alpha 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 i.p.) prevented toxicity and HIF-1alpha induction. In further studies, hepatocyte suspensions were incubated with APAP (1 mM) in the presence of an oxygen atmosphere. HIF-1alpha was induced at 1 h, prior to the onset of toxicity. Inclusion of cyclosporine A (10 microM), an inhibitor of mitochondrial permeability transition, oxidative stress, and toxicity, prevented the induction of HIF-1alpha. Thus, HIF-1alpha 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-1alpha in APAP toxicity.
缺氧诱导因子（HIF）控制参与血管生成、红细胞生成、糖酵解和细胞存活的基因转录。HIF-1α水平是HIF活性的关键决定因素。在给予小鼠毒性剂量对乙酰氨基酚（APAP，300mg/kg腹腔注射）并于1、2、4、8和12小时处死的情况下，检测其肝脏中HIF-1α的诱导情况。HIF-1α在1至12小时被诱导，且诱导发生在毒性发作之前。用N-乙酰半胱氨酸（1200mg/kg腹腔注射）对小鼠进行预处理可预防毒性和HIF-1α诱导。在进一步研究中，将肝细胞悬液在有氧气氛下与APAP（1mM）一起孵育。HIF-1α在1小时被诱导，早于毒性发作。加入环孢素A（10μM），一种线粒体通透性转换、氧化应激和毒性的抑制剂，可阻止HIF-1α的诱导。因此，HIF-1α在APAP毒性之前被诱导，且可在非缺氧条件下发生。数据表明氧化应激在APAP毒性中HIF-1α的诱导过程中起作用。
