基于肝毒性损伤模式筛选雷公藤主要肝毒性成分,BMC Complementary and Alternative Medicine

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基于肝毒性损伤模式筛选雷公藤主要肝毒性成分
BMC Complementary and Alternative Medicine Pub Date : 2023-01-10 , DOI: 10.1186/s12906-023-03836-w
Meng Li ₁ , Qiong Luo ₁ , Xi Chen ₂ , Furong Qiu ₃ , Yanyan Tao ₁ , Xin Sun _{1,

2} , Chenghai Liu _{1,

2,

4,

5}

Affiliation

雷公藤钩。F.（TwHF）是一种中药，广泛用于类风湿性关节炎的治疗。由于多器官毒性，特别是肝毒性，TwHF的应用受到限制。为了澄清肝毒性物质，斑马鱼、肝细胞和巨噬细胞被用于基于肝毒性损伤模式的筛选。本研究为进一步阐明TwHF的肝毒性机制提供了依据。首先，根据 TwHF 的化学类别选择了 12 种化合物。观察并计算斑马鱼肝脏的荧光面积和荧光强度。通过 CCK8 测定法检测两种肝细胞系的活力。骨髓来源的巨噬细胞中的 TNF-α 和 IL-1β mRNA 表达用于评估巨噬细胞活化，这是潜在的间接肝毒性的一个因素。最后，在小鼠体内验证了4种代表性成分的肝毒性特征。小白菊内酯、雷公藤内酯、雷公藤内酯、雷公藤苯 H、雷公藤酚、demethylzeylasteral、wilforlide A、雷公藤甲酸 A 和 regelidine 显着降低了斑马鱼肝脏的荧光面积和荧光强度。L-02 或 AML-12 细胞的活力被小白菊内酯、雷公藤内酯、雷公藤内酯、雷公藤酚、去甲基zeylasteral 和雷公藤三萜酸 A 显着抑制。巨噬细胞中的 1β mRNA 水平，而雷公藤酚内酯、hypodiolide 和 wilforine 显着降低 TNF-α 和 IL-1β mRNA 水平。三萜酸A，剂量为 10 mg/kg 的雷公藤酚和雷公藤苯 H 显着增加小鼠血清丙氨酸转氨酶和天冬氨酸转氨酶的水平，并加重肝脏炎症。小白菊内酯、雷公藤内酯、雷公藤内酯、雷公藤酚、去甲基zeylasteral、雷公藤三萜酸A和雷公藤苯H可能是TwFH的主要肝毒性成分。其中只有三萜酸A具有直接肝毒性。Triptobenzene H 通过激活巨噬细胞产生间接肝损伤。小白菊内酯、雷公藤内酯、雷公藤内酯、雷公藤酚、去甲基zeylasteral可直接或间接引起肝损伤。雷公藤三萜酸A和雷公苯H可能是TwFH的主要肝毒性成分。其中只有三萜酸A具有直接肝毒性。Triptobenzene H 通过激活巨噬细胞产生间接肝损伤。小白菊内酯、雷公藤内酯、雷公藤内酯、雷公藤酚、去甲基zeylasteral可直接或间接引起肝损伤。雷公藤三萜酸A和雷公苯H可能是TwFH的主要肝毒性成分。其中只有三萜酸A具有直接肝毒性。Triptobenzene H 通过激活巨噬细胞产生间接肝损伤。小白菊内酯、雷公藤内酯、雷公藤内酯、雷公藤酚、去甲基zeylasteral可直接或间接引起肝损伤。

"点击查看英文标题和摘要"

Screening of major hepatotoxic components of Tripterygium wilfordii based on hepatotoxic injury patterns

Tripterygium wilfordii Hook. F. (TwHF), a traditional Chinese medicine, is widely used in the treatment of rheumatoid arthritis. Due to multiorgan toxicity, particularly hepatotoxicity, the application of TwHF is restricted. To clarify the hepatotoxic substances, zebrafish, hepatocytes and macrophages were used for screening based on hepatotoxic injury patterns. This study provides a basis for further elucidation of the hepatotoxic mechanism of TwHF. First, 12 compounds were selected according to the chemical categories of TwHF. The fluorescence area and fluorescence intensity of zebrafish livers were observed and calculated. The viability of two hepatocyte lines was detected by CCK8 assay. TNF-α and IL-1β mRNA expression in bone marrow-derived macrophages was used to evaluate macrophage activation, a factor of potential indirect hepatotoxicity. Finally, the hepatotoxic characteristics of 4 representative components were verified in mice in vivo. Parthenolide, triptolide, triptonide, triptobenzene H, celastrol, demethylzeylasteral, wilforlide A, triptotriterpenic acid A and regelidine significantly reduced the fluorescence area and fluorescence intensity of zebrafish livers. The viability of L-02 or AML-12 cells was significantly inhibited by parthenolide, triptolide, triptonide, celastrol, demethylzeylasteral, and triptotriterpenic acid A. Parthenolide, triptolide, triptonide, celastrol, demethylzeylasteral and triptobenzene H significantly increased TNF-α and IL-1β mRNA levels in macrophages, while triptophenolide, hypodiolide and wilforine significantly reduced TNF-α and IL-1β mRNA levels. Triptotriterpenic acid A, celastrol and triptobenzene H at a dose of 10 mg/kg significantly increased the levels of mouse serum alanine aminotransferase and aspartate aminotransferase and aggravated liver inflammation. Parthenolide, triptolide, triptonide, celastrol, demethylzeylasteral, triptotriterpenic acid A and triptobenzene H might be the main hepatotoxic components of TwFH. Among them, only triptotriterpenic acid A presents direct hepatotoxicity. Triptobenzene H exerts indirect liver damage by activating macrophages. Parthenolide, triptolide, triptonide, celastrol, and demethylzeylasteral can directly and indirectly cause liver injury.

更新日期：2023-01-10

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