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Carbamazepine promotes specific stimuli-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury in mice.
Archives of Toxicology ( IF 4.8 ) Pub Date : 2019-11-01 , DOI: 10.1007/s00204-019-02606-3
Zhilei Wang 1, 2 , Guang Xu 1 , Xiaoyan Zhan 1 , Youping Liu 2 , Yuan Gao 3 , Nian Chen 2 , Yuming Guo 1 , Ruisheng Li 4 , Tingting He 5 , Xueai Song 5 , Ming Niu 1 , Jiabo Wang 1 , Zhaofang Bai 1, 5 , Xiaohe Xiao 1, 2, 5
Affiliation  

The occurrence of idiosyncratic drug-induced liver injury (IDILI) is a leading cause of post-marketing safety warnings and withdrawals of drugs. Carbamazepine (CBZ), widely used as an antiepileptic agent, could cause rare but severe idiosyncratic liver injury in humans. Although recent studies have shown that inflammasome is implicated in CBZ-induced hepatocellular injury in vitro, the precise pathogenesis of hepatotoxicity remains largely unexplored. Here we report that CBZ causes idiosyncratic liver injury through promoting specific stimuli-induced NLRP3 inflammasome activation. CBZ (40 μM) enhances NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) or nigericin, rather than SiO2, monosodium urate crystal or intracellular lipopolysaccharide (LPS). In addition, CBZ has no effect on NLRC4 or AIM2 inflammasome activation. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial event in the enhancement effect of CBZ on ATP- or nigericin-induced NLRP3 inflammasome activation. Moreover, the “C=C” on the seven-membered ring and “C=O” on the nitrogen of CBZ may be contribute to NLRP3 inflammasome hyperactivation and hepatotoxicity. Notably, in vivo data indicate that CBZ (50 mg/kg) causes liver injury in an LPS (2 mg/kg)-mediated susceptibility mouse model of IDILI, accompanied by an increase in caspase-1 activity and IL-1β production, whereas the combination of CBZ and LPS does not exhibit the effect in NLRP3-knockout mice. In conclusion, CBZ specifically promotes ATP- or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury. Our findings also suggest that CBZ may be avoided in patients with NLRP3 inflammasome activation-related diseases that are triggered by ATP or nigericin, which may be risk factors for IDILI.



中文翻译:

卡马西平促进特定刺激物诱导的NLRP3炎性小体活化,并引起小鼠特发性肝损伤。

特异药物性肝损伤(IDILI)的发生是上市后安全警告和药物停用的主要原因。卡马西平(CBZ)被广泛用作抗癫痫药,可能在人类中引起罕见但严重的特发性肝损伤。尽管最近的研究表明,炎症小体与体外CBZ诱导的肝细胞损伤有关,但肝毒性的确切发病机理仍未得到充分探索。在这里,我们报道CBZ通过促进特定的刺激诱导的NLRP3炎性体激活而引起特发性肝损伤。CBZ(40μM)增强了由三磷酸腺苷(ATP)或尼日利亚霉素而不是SiO 2触发的NLRP3炎性体活化,尿酸单钠晶体或细胞内脂多糖(LPS)。此外,CBZ对NLRC4或AIM2炎性体激活没有影响。从机制上讲,线粒体活性氧(mtROS)的协同诱导是CBZ对ATP或尼日利亚霉素诱导的NLRP3炎性体活化的增强作用中的关键事件。此外,七元环上的“ C = C”和CBZ氮上的“ C = O”可能有助于NLRP3炎性体过度活化和肝毒性。值得注意的是,体内数据表明CBZ(50 mg / kg)在LPS(2 mg / kg)介导的IDILI易感性小鼠模型中引起肝损伤,并伴有caspase-1活性和IL-1β产生的增加,而CBZ和LPS的组合在NLRP3基因敲除小鼠中不显示效果。综上所述,CBZ专门促进ATP或尼日利亚诱导的NLRP3炎性小体活化,并引起特发性肝损伤。我们的研究结果还表明,在由ATP或黑霉素触发的NLRP3炎性体激活相关疾病中,可以避免使用CBZ,这可能是IDILI的危险因素。

更新日期:2019-11-01
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