Modulation of serum growth factor signal transduction in Hepa 1-6 cells by acetaminophen:: An inhibition of c-myc expression, NF-κB activation, and Raf-1 kinase activity
Modulation of serum growth factor signal transduction in Hepa 1-6 cells by acetaminophen:: An inhibition of c-myc expression, NF-κB activation, and Raf-1 kinase activity
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DOI：
10.1093/toxsci/48.2.264
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发表时间：
1999-04-01
影响因子：
3.8
通讯作者：
Cohen, SD
中科院分区：
文献类型：
--
作者：
Boulares, HA;Giardina, C;Cohen, SD
对乙酰氨基酚（APAP）是一种广泛使用的止痛剂和解热剂，过量服用会导致严重的肝损伤。当细胞色素P450产生的APAP代谢物触发氧化应激并共价修饰靶蛋白时，APAP毒性产生。据报道，APAP还通过细胞色素P350非依赖性机制抑制细胞完成S期，这提高了APAP可能直接抑制肝再生和修复的可能性。在这里，我们表明，APAP还通过阻断与G 0-G1转换相关的许多事件来抑制Hepa 1-6细胞进入细胞周期。我们发现APAP抑制血清生长因子激活c-myc表达、NF-κ B DNA结合和Raf激酶。因此，APAP抑制细胞通过G1和S期的能力可能会干扰器官再生，从而加剧APAP引起的急性肝损伤。
Acetaminophen (APAP) is a widely used analgesic and antipyretic that can lead to severe liver damage when taken at excessive doses. APAP toxicity results when cytochrome P450-generated APAP metabolites trigger an oxidative stress and covalently modify target proteins. APAP has also been reported to inhibit cells from completing S-phase through a cytochrome P350-independent mechanism, raising the possibility that APAP may directly suppress liver regeneration and repair. Here we show that APAP also inhibits entrance of Hepa 1-6 cells into the cell cycle by blocking a number of events associated with the G0-G1 transition. We have found that APAP inhibits serum growth factor activation of c-myc expression, NF-kappa B DNA binding, and Raf kinase. Therefore, the ability of APAP to inhibit passage of cells through both G1 and S phases might interfere with organ regeneration and thus exacerbate acute liver damage caused by APAP.