Role of nitric oxide and nuclear factor-kappaB in the CYP2E1 potentiation of tumor necrosis factor alpha hepatotoxicity in mice.
Role of nitric oxide and nuclear factor-kappaB in the CYP2E1 potentiation of tumor necrosis factor alpha hepatotoxicity in mice.
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DOI：
10.1016/j.freeradbiomed.2008.11.001
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发表时间：
2009-02
影响因子：
7.4
通讯作者：
Defeng Wu;Cijie Xu;A. Cederbaum
中科院分区：
文献类型：
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作者：
Defeng Wu;Cijie Xu;A. Cederbaum
吡唑（pyrazole， PY）诱导小鼠CYP2E1增强了TNFα引起的肝毒性。我们评估了亚硝化和氧化应激以及NF-κB激活途径在这种肝损伤中的作用。iNOS抑制剂N-（3-氨基甲基）苄乙酰氨基胺（1400W）或抗氧化剂N-乙酰-l-半胱氨酸（NAC）可预防肝损伤。TNFα + PY处理引发肝脏自由基应激，增加脂质过氧化和谷胱甘肽水平降低，并引起线粒体损伤，表现为膜肿胀和细胞色素c释放升高。1400W和NAC可预防自由基应激和线粒体损伤。TNFα + PY处理可提高3-硝基酪氨酸加合物的形成，诱导肝脏NOS2；1400W和NAC阻止了这些变化。与野生型对照组相比，TNFα + PY处理的NOS2−/−小鼠的肝损伤和氧化应激程度较低。1400W和NAC均未改变CYP2E1活性或蛋白。JNK和p38MAPK的激活在TNFα + py处理的NOS2−/−小鼠中较弱，1400W和NAC阻断了野生型小鼠JNK和p38MAPK的激活。TNFα + PY组IKKα/β蛋白水平降低，而i - κ b α和i - κ b β蛋白水平升高。tnf - α单独作用可提高NF-κB DNA结合活性，tnf - α加PY可降低其结合活性。这些变化都被1400W和NAC阻断了。TNFα + PY可使NF-κB活化产物Bcl-2、Bcl-XL、clips、cFLIPL、Mn-SOD降低，1400W或NAC可使其恢复。我们得出结论，TNFα + CYP2E1诱导氧化/亚硝化应激，这在JNK或p38MAPK的激活和线粒体损伤中起作用。这些作用与NF-κB激活途径的钝化和保护因子的合成相结合，导致肝损伤。
Induction of CYP2E1 by pyrazole (PY) potentiated the hepatotoxicity induced by TNFα in mice. We evaluated the role of nitrosative and oxidative stress and the NF-κB activation pathway in this liver injury. The iNOS inhibitor N-(3-aminomethyl)benzylacetamindine (1400W) or the antioxidant N-acetyl-l-cysteine (NAC) prevented this liver injury. TNFα plus PY treatment triggered radical stress in the liver with increased lipid peroxidation and decreased glutathione and caused mitochondrial damage as reflected by elevated membrane swelling and cytochrome c release. The radical stress and mitochondrial damage were prevented by 1400W and NAC. TNFα plus PY treatment elevated 3-nitrotyrosine adduct formation and induced NOS2 in the liver; 1400W and NAC blocked these changes. A lower extent of liver injury and oxidative stress was found in NOS2−/−mice treated with TNFα plus PY compared with wild-type controls. Neither 1400W nor NAC modified CYP2E1 activity or protein. Activation of JNK and p38MAPK was weaker in TNFα plus PY-treated NOS2−/−mice and 1400W and NAC blocked the activation of JNK and p38MAPK in wild-type mice. IKKα/β protein levels were decreased by TNFα plus PY treatment, whereas IκBα and IκBβ protein levels were elevated compared with saline, PY, or TNFα alone. NF-κB DNA binding activity was increased by TNFα alone but lowered by TNFα plus PY. All these changes were blocked by 1400W and NAC. NF-κB activation products such as Bcl-2, Bcl-XL, cFLIPS, cFLIPL, and Mn-SOD were reduced by TNFα plus PY and restored by 1400W or NAC. We conclude that TNFα plus CYP2E1 induces oxidative/nitrosative stress, which plays a role in the activation of JNK or p38MAPK and mitochondrial damage. These effects combine with the blunting of the NF-κB activation pathways and the synthesis of protective factors to cause liver injury.