An in vitro comparison of the cytotoxic potential of selected dehydropyrrolizidine alkaloids and some N-oxides

• Published in: Toxicon (Oxford) 2015-04, Vol.97, p.36-45
• Main Authors: Field, Reuel A., Stegelmeier, Bryan L., Colegate, Steven M., Brown, Ammon W., Green, Benedict T.
• Format: Article
• Language: English
• Subjects: Alkaloids; Animal health; Animals; Carcinogenicity; Carcinogens; Cattle; Cell Line, Tumor; Cell Survival - drug effects; Chicken-CRL-2118; Chickens; Comparative-cytotoxicity; Cyclic N-Oxides - toxicity; Cytotoxins - toxicity; Dangerous; Exposure; HEK293 Cells; Hep G2 Cells; Hepatocellular-carcinoma; Human; Humans; In Vitro Techniques; Molecular Structure; Monocrotaline - chemistry; Monocrotaline - toxicity; Pilot Projects; Pyrrolizidine Alkaloids - chemistry; Pyrrolizidine Alkaloids - toxicity; Pyrrolizidine-alkaloid; Pyrrolizidine-alkaloid-N-oxide; Tetrazolium Salts; Thiazoles; Viability
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2015.02.001

Plants producing dehydropyrrolizidine alkaloids (DHPAs) are found throughout the world and they are dangerous to human and animal health. Several DHPAs are carcinogenic but only riddelliine has been classified as a potential human carcinogen by the National Toxicology Program. As DHPA-related carcinogenicity is probably linked to cytotoxicity, a model of CRL-2118 chicken hepatocyte cytotoxicity was developed to compare equimolar DHPA exposures between 19 and 300 μM. Alkaloid-related cytotoxicity was estimated using cytomorphology, cell viability reflected by mitochondrial function and cellular degeneration reflected by media lactate dehydrogenase activity. Lasiocarpine induced cytotoxicity and decreased cell viability in a concentration dependent manner at 24 h. At similar concentrations and exposures of 48 and 72 h, seneciphylline, senecionine, monocrotaline and riddelliine were cytotoxic. None of the DHPA-N-oxides were significantly cytotoxic at these concentrations. Using graphic analyses the median cytotoxic concentration (DHPA concentration that produced ½ the maximum response) were estimated. The estimated descending order of cytotoxicity was lasiocarpine, seneciphylline, senecionine, heliotrine, riddelliine, monocrotaline, riddelliine-N-oxide, lycopsamine, intermedine, lasiocarpine-N-oxide and senecionine-N-oxide. This comparison identifies DHPAs that were more cytotoxic than carcinogenic riddelliine. Additional studies to better characterize the carcinogenic potential of these alkaloids are essential to better determine the risk they each may pose for human and animal health. •Eleven dehydropyrrolizidine alkaloids were assessed for CRL-2118 cytotoxicity.•Highly toxic lasiocarpine, seneciphylline, senecionine and heliotrine were identified.•Medium toxicity alkaloids include riddelliine, monocrotaline and riddelliine N-oxide.•Alkaloids more cytotoxic than riddelliine should be tested for carcinogenic potential.