Acetaminophen hepatotoxicity and HIF-1α induction in acetaminophen toxicity in mice occurs without hypoxia.
Acetaminophen hepatotoxicity and HIF-1α induction in acetaminophen toxicity in mice occurs without hypoxia.
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DOI：
10.1016/j.taap.2011.02.005
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发表时间：
2011-05-01
影响因子：
3.8
通讯作者：
James LP
中科院分区：
文献类型：
--
作者：
Chaudhuri S;McCullough SS;Hennings L;Letzig L;Simpson PM;Hinson JA;James LP
HIF-1α是一种核因子，在控制血管生成的基因（包括血管内皮生长因子（VEGF））的转录中起重要作用。缺氧和氧化应激都是已知的诱导HIF-1α的机制。氧化应激和线粒体通透性转换（MPT）在小鼠对乙酰氨基酚（APAP）毒性中具有重要的机制。MPT可能是氧化应激的结果，并导致氧化应激的大幅增加。我们先前报道了APAP毒性小鼠中HIF-1α的诱导，并表明VEGF在APAP毒性后的肝细胞再生中很重要。进行以下研究以检查在小鼠中APAP毒性中缺氧与氧化应激对HIF-1α诱导的相对贡献。使用缺氧标志物哌莫硝唑的时程研究显示，在用APAP处理的B6 C3 F1小鼠中，1或2小时时哌莫硝唑没有染色。染色pimonidazole存在于中间带至门静脉周围区域在4，8，24和48小时，没有染色观察到小叶中心肝细胞，网站的毒性。随后使用MPT抑制剂环孢菌素A进行的研究表明，环孢菌素A（CYC; 10 mg/kg）在1和4 h时减少APAP处理小鼠中的HIF-1α诱导，并且不抑制APAP的代谢（肝脏非蛋白巯基和肝脏蛋白加合物水平的消耗）。这些数据表明，在APAP毒性的早期阶段，HIF-1α诱导是通过涉及MPT的机制继发于氧化应激。此外，APAP毒性不是由缺氧机制介导的。
HIF-1α is a nuclear factor important in the transcription of genes controlling angiogenesis including vascular endothelial growth factor (VEGF). Both hypoxia and oxidative stress are known mechanisms for the induction of HIF-1α. Oxidative stress and mitochondrial permeability transition (MPT) are mechanistically important in acetaminophen (APAP) toxicity in the mouse. MPT may occur as a result of oxidative stress and leads to a large increase in oxidative stress. We previously reported the induction of HIF-1α in mice with APAP toxicity and have shown that VEGF is important in hepatocyte regeneration following APAP toxicity. The following study was performed to examine the relative contribution of hypoxia versus oxidative stress to the induction of HIF-1α in APAP toxicity in the mouse. Time course studies using the hypoxia marker pimonidazole showed no staining for pimonidazole at 1 or 2 h in B6C3F1 mice treated with APAP. Staining for pimonidazole was present in the midzonal to periportal regions at 4, 8, 24 and 48 h and no staining was observed in centrilobular hepatocytes, the site of the toxicity. Subsequent studies with the MPT inhibitor cyclosporine A showed that cyclosporine A (CYC; 10 mg/kg) reduced HIF-1α induction in APAP treated mice at 1 and 4 h and did not inhibit the metabolism of APAP (depletion of hepatic non-protein sulfhydryls and hepatic protein adduct levels). The data suggest that HIF-1α induction in the early stages of APAP toxicity is secondary to oxidative stress via a mechanism involving MPT. In addition, APAP toxicity is not mediated by a hypoxia mechanism.
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影响因子：
4.1
作者：
Hinson, JA;Pike, SL;Mayeux, PR
通讯作者：
Mayeux, PR
影响因子：
4.3
作者：
Halestrap, AP;Connern, CP;Kerr, PM
通讯作者：
Kerr, PM
影响因子：
3.8
作者：
Copple, BL;Rondelli, CM;Roth, RA
通讯作者：
Roth, RA
DOI：
10.1016/j.bbrc.2006.02.143
发表时间：
2006-04-28
影响因子：
3.1
作者：
James, LP;Donahower, B;Hinson, JA
通讯作者：
Hinson, JA
影响因子：
3.8
作者：
Knight, TR;Kurtz, A;Jaeschke, H
通讯作者：
Jaeschke, H