Characterization of the cytotoxicity of selected Chelidonium alkaloids in rat hepatocytes. (1st September 2019)

• Record Type: Journal Article
• Authors: Gao, Lan; Schmitz, Hans-Joachim; Merz, Karl-Heinz; Schrenk, Dieter
• Is Part Of: Toxicology letters. Volume 311(2019)
• Page Start: 91
• Page End: 97
• Publication Date: 2019-09-01
• Subjects: CAL Chelidonium alkaloids -- DMEM-HG Dulbecco's Modified Eagle's Medium High Glucose -- DMEM-LG Dulbecco's Modified Eagle's Medium Low Glucose -- DMSO dimethyl sulfoxide -- DTNB 5, 5′-dithiobis(2-nitrobenzoic acid) -- FCS fetal calf serum -- G6P glucose-6-phosphate -- G6P-DH glucose-6-phosphate-dehydrogenase -- GSH reduced glutathione -- GSSG oxidized glutathione -- GSx total glutathione -- HBSS Hank's Balanced Salt Solution -- Pen/Strep penicillin/streptomycin -- TNB 5-thio-2-nitrobenzoic acid -- WEM William's E Medium; Alkaloids -- Chelidonium majus -- Hepatotoxicity -- Glutathione -- Papaveraceae -- Rat hepatocytes -- Sanguinarine; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.04.031
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Major Chelidonium majus alkaloids are cytotoxic in rat hepatocytes in primary culture. CAL differ widely in their cytotoxic potency, the cationic congeners chelerythrine, coptisine and sanguinarine being the most toxic ones. Sanguinarine decreased intracellular glutathione levels, while dihydrosanguinarine did not. Depletion of glutathione with menadione did not render the cells significantly more susceptible towards sanguinarine or dihydrosanguinarine. Calculations suggest that in previous animal experiments hepatic CAL levels were too low to elicit hepatotoxicity. Abstract: 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.