Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Institute of Heath & Medical Technology, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui Province, China.
Chem Res Toxicol. 2020 Jul 20;33(7):1960-1968. doi: 10.1021/acs.chemrestox.0c00141. Epub 2020 Jun 8.
Fraxinellone, a furanoid, is one of the bioactive and potentially hepatotoxic constituents from Turcz, which is extensively spread throughout Asian countries. This herb was reported to cause liver injury in clinical application. However, the mechanism behind is still not fully understood. This study mainly focused on the hepatotoxicity of fraxinellone and the underlying mechanism. The current study demonstrated that fraxinellone resulted in a significant elevation of serum alanine aminotransferase and aspartate aminotransferase in a dose-dependent manner in mice after oral administration. Pretreatment with ketoconazole for three successive days could significantly alleviate the hepatotoxicity of fraxinellone. Considering that fraxinellone has a structural alert of furan ring, it is believed that the hepatotoxicity caused by fraxinellone required cytochrome P450-mediated bioactivation. Bioactivation studies were subsequently carried out in vitro and in vivo. Fraxinellone was metabolized into -enedial intermediate, an electrophile that was prone to react with glutathione or -acetyl-lysine through 1,2- or 1,4-addition to form stable conjugates. Ketoconazole significantly inhibited the formation of the glutathione conjugates (M1 and M2) in microsomal incubation and similar finding was obtained in vivo. Phenotyping study indicated that CYP3A4 was the principal enzyme responsible for the bioactivation of fraxinellone. This study suggested that CYP3A4-mediated bioactivation plays an indispensable role in fraxinellone-induced hepatotoxicity. The work performed herein enables us to better understand the hepatotoxicity of fraxinellone as well as the mechanism behind.
水曲柳酮，一种呋喃型化合物，是广泛分布于亚洲国家的 Turcz 中的一种生物活性和潜在肝毒性成分。该草药在临床应用中已被报道会导致肝损伤。然而，其背后的机制尚未完全阐明。本研究主要关注水曲柳酮的肝毒性及其潜在机制。目前的研究表明，水曲柳酮经口服给药后，在小鼠体内呈剂量依赖性显著升高血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶。连续 3 天预先给予酮康唑可显著减轻水曲柳酮的肝毒性。鉴于水曲柳酮具有呋喃环的结构警示，认为水曲柳酮引起的肝毒性需要细胞色素 P450 介导的生物活化。随后在体外和体内进行了生物活化研究。水曲柳酮代谢为烯二醛中间体，一种亲电试剂，通过 1,2-或 1,4-加成容易与谷胱甘肽或乙酰赖氨酸反应，形成稳定的缀合物。酮康唑显著抑制了微粒体孵育中谷胱甘肽缀合物（M1 和 M2）的形成，在体内也得到了类似的发现。表型研究表明 CYP3A4 是负责水曲柳酮生物活化的主要酶。本研究表明，CYP3A4 介导的生物活化在水曲柳酮诱导的肝毒性中起着不可或缺的作用。本研究使我们能够更好地理解水曲柳酮的肝毒性及其背后的机制。
