Characterization of the cytotoxicity of selected Chelidonium alkaloids in rat hepatocytes
| Autor: | Karl-Heinz Merz, Dieter Schrenk, Lan Gao, Hans-Joachim Schmitz |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Coptisine Berberine Primary Cell Culture Pharmacology Toxicology Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Alkaloids 0302 clinical medicine Animals Chelidonium Sanguinarine Rats Wistar Cytotoxicity Cells Cultured Benzophenanthridines Dose-Response Relationship Drug Molecular Structure biology Chemistry General Medicine Glutathione Isoquinolines biology.organism_classification stomatognathic diseases 030104 developmental biology Chelerythrine Toxicity Chelidonine Hepatocytes Chemical and Drug Induced Liver Injury 030217 neurology & neurosurgery |
| Zdroj: | Toxicology Letters. 311:91-97 |
| ISSN: | 0378-4274 |
| DOI: | 10.1016/j.toxlet.2019.04.031 |
| Popis: | 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 (EC20 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. |
| Databáze: | OpenAIRE |
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