Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α
Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α
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DOI：
10.1152/ajpgi.00304.2001
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发表时间：
2002-02-01
影响因子：
4.5
通讯作者：
Czaja, MJ
中科院分区：
文献类型：
--
作者：
Liu, HL;Jones, BE;Czaja, MJ
肝细胞对肿瘤坏死因子-α（TNF-α）介导的细胞死亡敏感的机制尚不清楚。肝细胞氧化应激的增加，如肝细胞色素P-450 2 E1（CYP 2 E1）过度表达可能促进TNF-α死亡。TNF-α处理具有差异CYP 2 E1表达的肝细胞系表明，CYP 2 E1的过表达将肝细胞TNF-α反应从增殖转化为凋亡和坏死细胞死亡。尽管存在核因子-kappaB转录活性水平增加，但仍发生死亡，并与脂质过氧化反应增加和GSH耗竭相关。CYP 2 E1过表达肝细胞的c-Jun氨基末端激酶（JNK）活性的基础水平和TNF-α诱导水平增加，以及TNF-α刺激后JNK活化延长。抗氧化剂或显性阴性c-Jun的腺病毒表达可抑制CYP 2 E1过表达对TNF-α诱导的细胞死亡的致敏作用。CYP 2 E1表达的增加使肝细胞对c-Jun介导的TNF-α毒性和压倒性的氧化应激敏感。由CYP 2 E1过表达引起的细胞内氧化应激的慢性增加可能是肝细胞对肝脏疾病中的TNF-α毒性敏感的机制。
The mechanisms underlying hepatocyte sensitization to tumor necrosis factor-alpha (TNF-alpha)-mediated cell death remain unclear. Increases in hepatocellular oxidant stress such as those that occur with hepatic overexpression of cytochrome P-450 2E1 (CYP2E1) may promote TNF-alpha death. TNF-alpha treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-alpha response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-kappaB transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-alpha-induced levels of c-Jun NH2-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-alpha stimulation. Sensitization to TNF-alpha-induced cell death by CYP2E1 overexpression was inhibited by antioxidants or adenoviral expression of a dominant-negative c-Jun. Increased CYP2E1 expression sensitized hepatocytes to TNF-alpha toxicity mediated by c-Jun and overwhelming oxidative stress. The chronic increase in intracellular oxidant stress created by CYP2E1 overexpression may serve as a mechanism by which hepatocytes are sensitized to TNF-alpha toxicity in liver disease.