Jiang Weifan, Dai Tianming, Xie Shuilin, Ding Lan, Huang Lizhen, Dai Renke
School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital, The Fourth Affiliated Hospital of Medical College, Jinan University, Guangzhou 510220, China.
Int Immunopharmacol. 2020 Sep;86:106723. doi: 10.1016/j.intimp.2020.106723. Epub 2020 Jun 30.
Diclofenac (DCF) is a widely used nonsteroidal anti-inflammatory drug, but it comes with a high risk of drug-induced liver injury (DILI). Despite the quinone-imine adduct pathways, the immunotoxicity is recently considered as another factor for DILI. However, such immune responses are still elusive. In the present study, investigation of the immune response in the acute hepatotoxicity model of TgCYP3A4/hPXR-humanized mice was conducted by administration of DCF and DCF metabolites, respectively. In a single dose intraperitoneal injection of 80 mg/kg DCF, the pharmacokinetic results showed the major DCF metabolites, including 4'-hydroxy-diclofenac (4'-OH-DCF), 5-hydroxy-diclofenac (5-OH-DCF) and diclofenac glucuronide (DCF-G) were generated after DCF treatment. Not only DCF, but those DCF metabolites could also directly cause different degrees of acute liver injury as significantly increased the serum ALT levels in a short time period in the TgCYP3A4/hPXR-humanized mice. Furthermore, the three DCF metabolites could directly stimulate the significant elevation of serum immune-related factors in varying degrees. Transcriptome analysis revealed the differentially expressed genes in the liver of DCF-G treated mice were mostly involved with the "immune system process" and "cell death" and related to "IL-17 signaling pathway" and "TNF-α signaling pathway", but 5-OH-DCF had little effect on the expressions of those genes. These results indicate that the metabolite DCF-G plays an important role in the activation of the hepatic immune system, which might be involved in the pathogenesis of DCF-induced acute liver injury.
双氯芬酸（DCF）是一种广泛使用的非甾体抗炎药，但它具有较高的药物性肝损伤（DILI）风险。尽管存在醌亚胺加合物途径，但免疫毒性最近被认为是DILI的另一个因素。然而，这种免疫反应仍然难以捉摸。在本研究中，分别通过给予DCF和DCF代谢物，对TgCYP3A4/hPXR人源化小鼠急性肝毒性模型中的免疫反应进行了研究。在单次腹腔注射80mg/kg DCF后，药代动力学结果显示，DCF治疗后产生了主要的DCF代谢物，包括4'-羟基双氯芬酸（4'-OH-DCF）、5-羟基双氯芬酸（5-OH-DCF）和双氯芬酸葡萄糖醛酸苷（DCF-G）。不仅DCF，而且这些DCF代谢物也能直接导致不同程度的急性肝损伤，因为它们在短时间内显著提高了TgCYP3A4/hPXR人源化小鼠的血清ALT水平。此外，这三种DCF代谢物能不同程度地直接刺激血清免疫相关因子显著升高。转录组分析显示，DCF-G处理小鼠肝脏中差异表达的基因大多与“免疫系统过程”和“细胞死亡”有关，且与“IL-17信号通路”和“TNF-α信号通路”相关，但5-OH-DCF对这些基因的表达影响很小。这些结果表明，代谢物DCF-G在肝脏免疫系统的激活中起重要作用，这可能参与了DCF诱导的急性肝损伤的发病机制。
