NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou, 510515, China.
Hunter Biotechnology, Inc., Hangzhou, 310051, China.
Toxicol Lett. 2022 Jan 1;354:1-13. doi: 10.1016/j.toxlet.2021.10.011. Epub 2021 Oct 28.
Aurantio-obtusin (AO) is a major anthraquinone (AQ) compound derived from Cassiae semen (CS). Although pharmacological studies have shown that the CS extracts can serve as effective agents in preclinical and clinical practice, AQ-induced hepatotoxicity in humans has attracted widespread attention. To explore whether AO induces hepatotoxicity and its underlying mechanisms, we exposed larval zebrafish and mice to AO. We found that AO delayed yolk sac absorption, and increased liver area and inflammation in the larval zebrafish. This inflammation was manifested as an increase in liver neutrophils and the up-regulated mRNA expression of interleukin-6 (Il-6) and tumor necrosis factor-α (Tnf-α) in the larval zebrafish. Furthermore, a pharmacokinetics study showed that AO was quickly absorbed into the blood and rapidly metabolized in the mice. Of note, AO induced hepatotoxicity in a gender-dependent manner, characterized by liver dysfunction, increased hepatocyte necrosis with inflammatory infiltration, and up-regulated mRNAs of Il-6, Tnf-α and monocyte chemotactic protein 1(Mcp1) in the female mice after 28-day oral administration. It also highlighted that AO triggered NOD-like receptor protein (NLRP) signaling in the female mice, as evidenced by the increased NLRP3, Caspase-1, pro-IL-1β, IL-1β and IL-18. Finally, we found that AO led to a significant increase in potassium calcium-activated channel, subfamily N, member 4 (KCNN4) and reactive oxygen species (ROS) levels, along with decreased nuclear factor kappa B p65 (NF-κB p65), in the female mouse livers. In conclusion, AO induced hepatotoxicity by activating NLRP3 inflammasome signaling, at least in part, through increased KCNN4 and ROS production, and NF-κB inhibition.
橙酮（AO）是一种主要的蒽醌（AQ）化合物，来源于决明子（CS）。尽管药理学研究表明 CS 提取物可以作为临床前和临床实践中的有效药物，但 AQ 诱导的人类肝毒性引起了广泛关注。为了探讨 AO 是否诱导肝毒性及其潜在机制，我们将 AO 暴露于幼虫斑马鱼和小鼠中。我们发现 AO 延迟了卵黄囊吸收，并增加了幼虫斑马鱼的肝脏面积和炎症。这种炎症表现为肝脏中性粒细胞增加，以及幼虫斑马鱼中白细胞介素 6（Il-6）和肿瘤坏死因子-α（Tnf-α）的 mRNA 表达上调。此外，药代动力学研究表明，AO 迅速被吸收到血液中，并在小鼠体内迅速代谢。值得注意的是，AO 以性别依赖的方式诱导肝毒性，其特征是肝功能障碍、肝实质细胞坏死伴炎症浸润增加，以及口服 28 天后雌性小鼠 Il-6、Tnf-α和单核细胞趋化蛋白 1（Mcp1）的 mRNA 上调。这也强调了 AO 在雌性小鼠中触发了 NOD 样受体蛋白（NLRP）信号，证据是 NLRP3、Caspase-1、前白细胞介素 1β（pro-IL-1β）、白细胞介素 1β（IL-1β）和白细胞介素 18（IL-18）增加。最后，我们发现 AO 导致雌性小鼠肝脏中钾钙激活通道亚家族 N 成员 4（KCNN4）和活性氧（ROS）水平显著增加，同时核因子 kappa B p65（NF-κB p65）减少。总之，AO 通过增加 KCNN4 和 ROS 产生以及 NF-κB 抑制，至少部分通过激活 NLRP3 炎性体信号来诱导肝毒性。
