山茱萸中环烯醚萜苷类成分肝毒性的差异与其代谢激活效率相关。

Difference in hepatotoxicity of furan-containing components in cortex dictamni correlates the efficiency of their metabolic activation.

机构信息

State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, Guizhou 550004, PR China; School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550004, PR China; School of Pharmacy, Guizhou Medical University, Guiyang, Guizhou 550004, PR China; Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang, Guizhou 550004, PR China.

出版信息

Phytomedicine. 2023 Jun;114:154778. doi: 10.1016/j.phymed.2023.154778. Epub 2023 Mar 18.

DOI:10.1016/j.phymed.2023.154778

PMID:36996529

Abstract

BACKGROUND

Cortex Dictamni (CD) has been associated with an increased risk of liver injury, which may be attributable to the metabolic activation of its furan-containing components (FCC). However, the hepatotoxic potencies of these FCCs and the mechanisms behind the differences in their toxicity intensity remain unknown.

METHODS

The constituents of CD extract were determined by LC-MS/MS. Potentially toxic FCCs were screened by a previously published method. Hepatotoxicity of potentially toxic FCCs was evaluated in cultured mouse primary hepatocytes and mice. The ability to deplete hepatic glutathione (GSH), along with the formation of the corresponding GSH conjugates, resulting from the metabolic activation was determined ex vivo in mice. Intrinsic clearance rates (CLV/K) were assessed by a microsome-bases assay.

RESULTS

A total of 18 FCCs were detected in CD extract. Among them, four FCCs, including rutaevin (RUT), limonin (LIM), obacunone (OBA) and fraxinellone (FRA) were found to be bioactivated in microsomal incubations. Only FRA displayed significant hepatotoxicity in vitro and in vivo. Similarly, FRA caused GSH depletion and GSH conjugation the most in vivo. The order of CL for the four FCCs was FRA>>OBA>LIM>RUT.

CONCLUSION

FRA is the major toxic FCC component of hepatotoxic CD extract. The hepatotoxicity of FCCs is closely related to the efficiency of their metabolic activation.

摘要

背景

桑白皮（CD）与肝损伤风险增加有关，这可能归因于其含呋喃成分（FCC）的代谢激活。然而，这些 FCC 的肝毒性强度及其毒性差异背后的机制尚不清楚。

方法

采用 LC-MS/MS 法测定 CD 提取物的成分。采用先前发表的方法筛选潜在毒性 FCC。在培养的小鼠原代肝细胞和小鼠中评价潜在毒性 FCC 的肝毒性。通过在小鼠体内测定代谢激活导致的肝谷胱甘肽（GSH）耗竭以及相应 GSH 缀合物的形成，来确定其能力。通过基于微粒体的测定法评估内在清除率（CLV/K）。

结果

在 CD 提取物中检测到 18 种 FCC。其中，四种 FCC，包括桑皮苷 A（RUT）、柠檬苦素（LIM）、莪术呋喃二酮（OBA）和瑞香素（FRA），在微粒体孵育中被发现具有生物活性。只有 FRA 在体外和体内均表现出明显的肝毒性。同样，FRA 在体内引起的 GSH 耗竭和 GSH 缀合最多。四种 FCC 的 CL 顺序为 FRA>>OBA>LIM>RUT。