CREBH determines the severity of sulpyrine-induced fatal shock.
CREBH determines the severity of sulpyrine-induced fatal shock.
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DOI：
10.1371/journal.pone.0055800
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Takeda K
中科院分区：
文献类型：
--
作者：
Kamiyama N;Yamamoto M;Saiga H;Ma JS;Ohshima J;Machimura S;Sasai M;Kimura T;Ueda Y;Kayama H;Takeda K
尽管吡唑啉酮衍生物安乃近被广泛用作解热镇痛药，但也有报道称其副作用包括致命性休克。然而，这种严重副作用背后的分子机制尚不清楚。在此，我们报道肝脏中高表达的转录因子CREBH在安乃近诱导小鼠致命性休克中发挥重要作用。 CREBH 缺陷小鼠对实验性致命的安乃近休克具有抵抗力。我们发现，CREBH 缺陷小鼠肝脏中参与安乃近代谢的细胞色素 P450 2B (CYP2B) 家族基因由安乃近诱导的表达严重受损。此外，在CREBH缺陷的肝脏中引入CYP2B可恢复对安乃近的敏感性。此外，CREBH 的异位表达上调了 CYP2B10 启动子活性，并且野生型小鼠体内 CREBH 的敲低赋予了对致命安乃近休克的显着抵抗力。这些数据表明，CREBH 是 CYP2B 的正调节剂，响应安乃近给药，这可能导致致命的休克。
Although the pyrazolone derivative sulpyrine is widely used as an antipyretic analgesic drug, side effects, including fatal shock, have been reported. However, the molecular mechanism underlying such a severe side effect is largely unclear. Here, we report that the transcription factor CREBH that is highly expressed in the liver plays an important role in fatal shock induced by sulpyrine in mice. CREBH-deficient mice were resistant to experimental fatal sulpyrine shock. We found that sulpyrine-induced expression of cytochrome P450 2B (CYP2B) family genes, which are involved in sulpyrine metabolism, in the liver was severely impaired in CREBH-deficient mice. Moreover, introduction of CYP2B in CREBH-deficient liver restored susceptibility to sulpyrine. Furthermore, ectopic expression of CREBH up-regulated CYP2B10 promoter activity, and in vivo knockdown of CREBH in wild-type mice conferred a significant resistance to fatal sulpyrine shock. These data demonstrate that CREBH is a positive regulator of CYP2B in response to sulpyrine administration, which possibly results in fatal shock.
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