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Cytochrome P450-Mediated Bioactivation: Implication for the Liver Injury Induced by Fraxinellone, A Bioactive Constituent from Dictamni Cortex.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-06-02 , DOI: 10.1021/acs.chemrestox.0c00141 Haining Zhou 1 , Qingwang Liu 2 , Juan Zhang 1 , Jianning Yao 1 , Chunfeng Wang 1 , Yanzhen Zhang 1 , Yanle Li 1 , Xuexiu Zhang 1 , Lianfeng Zhang 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-06-02 , DOI: 10.1021/acs.chemrestox.0c00141 Haining Zhou 1 , Qingwang Liu 2 , Juan Zhang 1 , Jianning Yao 1 , Chunfeng Wang 1 , Yanzhen Zhang 1 , Yanle Li 1 , Xuexiu Zhang 1 , Lianfeng Zhang 1
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Fraxinellone, a furanoid, is one of the bioactive and potentially hepatotoxic constituents from Dictamnus dasycarpus 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 cis-enedial intermediate, an electrophile that was prone to react with glutathione or N-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.
中文翻译：
细胞色素P450介导的生物激活：对Fraxinellone（一种来自Dictamni Cortex的生物活性成分）诱导的肝损伤的影响。
呋喃酮类Fraxinellone是来自Dictamnus dasycarpus的生物活性成分和潜在的肝毒性成分Turcz，广泛分布于整个亚洲国家。据报道这种草药在临床应用中会引起肝损伤。但是，背后的机制仍未完全理解。这项研究主要侧重于氟辛内酯的肝毒性及其潜在机制。当前的研究表明，在口服后，fraxinellone导致小鼠血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶显着升高，呈剂量依赖性。连续三天用酮康唑进行预处理可以显着减轻fraxinellone的肝毒性。考虑到fraxinellone具有呋喃环的结构警觉，据信由fraxinellone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激活研究。Fraxinellone被代谢为顺式-烯丙基中间体，一种亲电子试剂，易于通过添加1,2-或1,4-与谷胱甘肽或N-乙酰基赖氨酸反应形成稳定的结合物。酮康唑在微粒体温育中显着抑制了谷胱甘肽结合物（M1和M2）的形成，并且在体内获得了类似的发现。表型研究表明，CYP3A4是导致fraxinellone生物活化的主要酶。这项研究表明CYP3A4介导的生物激活在fraxinellone诱导的肝毒性中起着不可或缺的作用。本文进行的工作使我们能够更好地了解六甲新酮的肝毒性及其背后的机制。
更新日期：2020-07-20
中文翻译：
细胞色素P450介导的生物激活：对Fraxinellone（一种来自Dictamni Cortex的生物活性成分）诱导的肝损伤的影响。
呋喃酮类Fraxinellone是来自Dictamnus dasycarpus的生物活性成分和潜在的肝毒性成分Turcz，广泛分布于整个亚洲国家。据报道这种草药在临床应用中会引起肝损伤。但是，背后的机制仍未完全理解。这项研究主要侧重于氟辛内酯的肝毒性及其潜在机制。当前的研究表明，在口服后，fraxinellone导致小鼠血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶显着升高，呈剂量依赖性。连续三天用酮康唑进行预处理可以显着减轻fraxinellone的肝毒性。考虑到fraxinellone具有呋喃环的结构警觉，据信由fraxinellone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激活研究。Fraxinellone被代谢为顺式-烯丙基中间体，一种亲电子试剂，易于通过添加1,2-或1,4-与谷胱甘肽或N-乙酰基赖氨酸反应形成稳定的结合物。酮康唑在微粒体温育中显着抑制了谷胱甘肽结合物（M1和M2）的形成，并且在体内获得了类似的发现。表型研究表明，CYP3A4是导致fraxinellone生物活化的主要酶。这项研究表明CYP3A4介导的生物激活在fraxinellone诱导的肝毒性中起着不可或缺的作用。本文进行的工作使我们能够更好地了解六甲新酮的肝毒性及其背后的机制。
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