Food Chemistry and Toxicology, Faculty of Chemistry, University of Kaiserslautern, Kaiserslautern, Germany.
Food Chemistry and Toxicology, Faculty of Chemistry, University of Kaiserslautern, Kaiserslautern, Germany.
Toxicol Lett. 2019 Sep 1;311:91-97. doi: 10.1016/j.toxlet.2019.04.031. Epub 2019 May 1.
Phytomedicinal preparations containing extracts of the plant Chelidonium majus (Greater Celandine) have been used in the therapy of upper abdominal disorders. C. majus alkaloids (CAL) were suspected to be responsible for reported cases of liver symptoms including cases of acute liver failure in patients upon treatment with certain C. majus preparations. Based on these reports, a safe oral daily dose limit of not more than 2.5 mg CAL was established in the EU. However, C. majus extracts and individual CAL were not able to elicit similar adverse effects when given orally to pigs or rats. We found that CAL differ considerably in their cytotoxicity in rat hepatocytes in culture. The cationic congeners chelerythrine, coptisine and sanguinarine were the most toxic ones (EC values ≤2 μM) while the neutral congeners chelidonine, dihydrosanguinarine and protopine were less toxic, with a rank order of toxicity of coptisine > chelerythrine > sanguinarine > chelidonine > protopine > dihydrosanguinarine. Calculation of octanol-water partition coefficients revealed that the most cytotoxic CAL in hepatocytes were the cationic polar ones. At cytotoxic concentrations sanguinarine led to a marked decrease in reduced and oxidized intracellular glutathione while the much less cytotoxic dihydrosanguinarine did not. After glutathione depletion with menadione, CAL toxicity was only slightly enhanced. Comparison of the cytotoxic concentrations to reported liver levels in experimental animals suggests that the latter were too low to cause hepatotoxicity, probably due to an extremely low oral availability of certain CAL.
含有 Chelidonium majus（黄连）植物提取物的植物药制剂已用于治疗上腹部疾病。Chelidonium majus 生物碱（CAL）被怀疑是导致报告的肝脏症状的原因，包括某些 Chelidonium majus 制剂治疗的患者出现急性肝功能衰竭的病例。基于这些报告，欧盟确定了每日口服不超过 2.5mg CAL 的安全剂量限制。然而，当将 C. majus 提取物和单个 CAL 口服给予猪或大鼠时，它们不能引起类似的不良反应。我们发现，CAL 在培养的大鼠肝细胞中的细胞毒性差异很大。阳离子同系物 Chelerythrine、Coptisine 和血根碱（EC 值≤2μM）毒性最强，而中性同系物 Chelidone、二氢血根碱和原阿片碱毒性较弱，毒性顺序为 Coptisine > Chelerythrine > Sanguinarine > Chelidone > Protopine > Dihydrosanguinarine。计算辛醇-水分配系数表明，在肝细胞中最具细胞毒性的 CAL 是阳离子极性化合物。在细胞毒性浓度下，血根碱导致还原型和氧化型细胞内谷胱甘肽明显减少，而毒性小得多的二氢血根碱则没有。用亚甲二氢叶酸还原酶抑制剂 menadione 耗尽谷胱甘肽后，CAL 毒性仅略有增强。将细胞毒性浓度与实验动物报告的肝脏水平进行比较表明，后者太低而不会引起肝毒性，可能是由于某些 CAL 的口服生物利用度极低。
