Tu Can, Gao Yuan, Song Di, Niu Ming, Ma Run-Ran, Zhou Ming-Xi, He Xian, Xiao Xiao-He, Wang Jia-Bo
Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
Front Pharmacol. 2021 Sep 23;12:693928. doi: 10.3389/fphar.2021.693928. eCollection 2021.
Early identification of individuals susceptible to idiosyncratic drug-induced liver injury (IDILI) is a challenging unmet demand. Diclofenac, one of the most widely available over-the-counter drugs for pain management worldwide, may induce liver dysfunction, acute liver failure, and death. Herein, we report that diclofenac-related hepatobiliary adverse reactions occurred more frequently in cases with immune activation. Furthermore, experiments with rats demonstrated divergent hepatotoxicity responses in individuals exposed to diclofenac, and modest inflammation potentiated diclofenac-induced liver injury. Susceptible rats had unique plasma metabolomic characteristics, and as such, the metabolomic approach could be used to distinguish susceptible individuals. The 23 identified susceptibility-related metabolites were enriched by several metabolic pathways related to acute-phase reactions of immunocytes and inflammatory responses, including sphingolipid, tyrosine, phenylalanine, tryptophan, and lipid metabolism pathways. This finding implies a mechanistic role of metabolic and immune disturbances affects susceptibility to diclofenac-IDILI. Further nine metabolite biomarkers with potent diagnostic capabilities were identified using receiver operating characteristic curves. These findings elucidated the potential utility of metabolomic biomarkers to identify individuals susceptible to drug hepatotoxicity and the underlying mechanism of metabolic and immune disturbances occurring in IDILI.
早期识别易发生特异质性药物性肝损伤（IDILI）的个体是一项具有挑战性且未得到满足的需求。双氯芬酸是全球最广泛使用的非处方止痛药物之一，可能会导致肝功能障碍、急性肝衰竭甚至死亡。在此，我们报告免疫激活患者中双氯芬酸相关的肝胆不良反应更为常见。此外，大鼠实验表明，接触双氯芬酸的个体具有不同的肝毒性反应，适度的炎症会加剧双氯芬酸诱导的肝损伤。易感大鼠具有独特的血浆代谢组学特征，因此，代谢组学方法可用于区分易感个体。已鉴定出的23种与易感性相关的代谢物通过与免疫细胞急性期反应和炎症反应相关的几种代谢途径得以富集，包括鞘脂、酪氨酸、苯丙氨酸、色氨酸和脂质代谢途径。这一发现表明代谢和免疫紊乱在双氯芬酸-IDILI易感性中具有机制性作用。使用受试者工作特征曲线进一步鉴定出了9种具有强大诊断能力的代谢物生物标志物。这些发现阐明了代谢组学生物标志物在识别药物肝毒性易感个体方面的潜在用途以及IDILI中发生的代谢和免疫紊乱的潜在机制。
