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A major source of human exposure is thought to be cross-contamination of food, feed and phytomedicines with PA plants. In humans, laboratory and farm animals, certain PAs exert pronounced liver toxicity and can induce malignant liver tumors in rodents. Here, we investigated the cytotoxicity and genotoxicity of eleven PAs belonging to different structural classes. Although all PAs were negative in the fluctuation Ames test in <jats:italic>Salmonella<\/jats:italic>, they were cytotoxic and induced micronuclei in human HepG2 hepatoblastoma cells over-expressing human cytochrome P450 3A4. Lasiocarpine and cyclic diesters except monocrotaline were the most potent congeners both in cytotoxicity and micronucleus assays with concentrations below 3\u00a0\u03bcM inducing a doubling in micronuclei counts. Other open di-esters and all monoesters exhibited weaker or much weaker geno- and cytotoxicity. The findings were in agreement with recently suggested interim Relative Potency (iREP) factors with the exceptions of europine and monocrotaline. A more detailed micronuclei analysis at low concentrations of lasiocarpine, retrorsine or senecionine indicated that pronounced hypolinearity of the concentration\u2013response curves was evident for retrorsine and senecionine but not for lasiocarpine. Our findings show that the genotoxic and cytotoxic potencies of PAs in a human hepatic cell line vary in a structure-dependent manner. Both the low potency of monoesters and the shape of prototype concentration\u2013response relationships warrant a substance- and structure-specific approach in the risk assessment of PAs.<\/jats:p>","DOI":"10.1007\/s00204-020-02895-z","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T16:03:19Z","timestamp":1599753799000},"page":"4159-4172","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Structure-dependent genotoxic potencies of selected pyrrolizidine alkaloids in metabolically competent HepG2 cells"],"prefix":"10.1007","volume":"94","author":[{"given":"Lukas","family":"Rutz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Heiner","family":"K\u00fcpper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7717-5533","authenticated-orcid":false,"given":"Dieter","family":"Schrenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,10]]},"reference":[{"key":"2895_CR1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0887-2333(99)00007-7","volume":"13","author":"E Alexandre","year":"1999","unstructured":"Alexandre E, David P, Viollon C, Wolf P, Jaeck D, Azimzadeh A, Nicod L, Boudjema K, Richert L (1999) Expression of cytochromes P-450 2E1, 3A4 and 1A1\/1A2 in growing and confluent human HepG2 hepatoma cells - effect of ethanol. 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