Effect of phenobarbital on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-kappaB.
Effect of phenobarbital on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-kappaB.
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DOI：
10.1016/j.taap.2007.09.019
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发表时间：
2008-02
影响因子：
3.8
通讯作者：
J. Tharappel;B. Spear;H. Glauert
中科院分区：
文献类型：
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作者：
J. Tharappel;B. Spear;H. Glauert
苯巴比妥（PB）是肝脏中一种无基因毒性的肿瘤启动子。PB发挥促瘤作用的机制之一是诱导氧化应激。我们之前发现给药PB增加了肝脏NF-κB DNA结合活性。在本研究中，我们验证了PB对细胞增殖和凋亡的影响依赖于NF-κB的假设。我们使用了NF-κB p50亚基缺失的小鼠模型；先前的研究发现p50−/−小鼠对多氯联苯或过氧化物酶体增殖剂诱导肝细胞增殖的敏感性较低。小鼠（p50−/−和野生型B6129）分别饲喂对照饲粮和含0.05% PB的饲粮3、10和34天。实验结束时，对小鼠实施安乐死，取出肝脏进行处理。PB在第3天和第10天（但在第34天没有）增加了细胞增殖，但NF-κB p50亚基的缺失并未抑制这种增加。p50−/−小鼠在第3天（仅饲喂PB的小鼠）和第34天的时间点细胞增殖率较高。PB在3 d后降低肝细胞凋亡，10 d后略有降低，34 d后无影响。NF-κB p50亚基的缺失不影响PB对细胞凋亡的作用。在p50−/−小鼠中，与野生型小鼠相比，凋亡在3天和10天后增加，但在34天后未见影响。NF-κ b调控基因TNF-α的肝脏表达与肝细胞增殖数据的相关性大于与肝细胞凋亡的相关性，并且不因p50亚基的缺失而降低。这些发现表明，在给药后34天内，PB对肝细胞增殖或凋亡的改变并不需要NF-κB的p50亚基。
Phenobarbital (PB) is a nongenotoxic tumor promoter in the liver. One mechanism by which PB may exert its tumor promoting activity is by inducing oxidative stress. We previously found that PB administration increased hepatic NF-κB DNA binding activity. In this study we examined the hypothesis that the effects of PB on cell proliferation and apoptosis are dependent on NF-κB. We used a mouse model that is deficient in the p50 subunit of NF-κB; previous studies had found that p50−/− mice were less sensitive to the induction of hepatic cell proliferation by PCBs or peroxisome proliferators. Mice (p50−/− and wild-type B6129) were fed a control diet or one containing 0.05% PB for 3, 10 or 34 days. At the end of the experiment, the mice were euthanized and livers removed and processed. PB increased cell proliferation at 3 and 10 days (but not at 34 days), but the deletion of the NF-κB p50 subunit did not inhibit these increases. p50−/− Mice had higher cell proliferation at the 3 day (only in mice fed PB) and 34-day timepoints. PB decreased hepatocyte apoptosis after 3 days, slightly decreased it after 10 days, and did not affect it after 34 days. The deletion of the NF-κB p50 subunit did not influence PB's effect on apoptosis. In p50−/− mice, apoptosis was increased after 3 or 10 days compared to wild-type mice, but no effect was seen after 34 days. The hepatic expression of the NF-κB-regulated gene TNF-α correlated more with the hepatic cell proliferation data than with hepatic apoptosis, and was not decreased by the deletion of the p50 subunit. These findings show that the p50 subunit of NF-κB is not required for the alteration of hepatocyte proliferation or apoptosis by PB up to 34 days after its administration.