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• W2943232094 abstract "Pyrrolizidine alkaloids (PAs) are hepatotoxic and specifically damage hepatic sinusoidal endothelial cells (HSECs) via cytochrome P450 enzymes (CYPs)-mediated metabolic activation. Due to the lack of CYPs in HSECs, currently there is no suitable cell model for investigating PA-induced HSEC injury. This study aimed to establish a two-layer transwell co-culture model that mimics hepatic environment by including HepaRG hepatocytes and HSECs to evaluate cytotoxicity of PAs on their major target HSECs. In this model, PAs were metabolically activated by CYPs in HepaRG hepatocytes to generate reactive pyrrolic metabolites, which react with co-cultured HSECs leading to HSEC damage. Three representative PAs, namely retrorsine, monocrotaline, and clivorine, induced significant concentration-dependent cytotoxicity in HSECs in the co-culture model, but did no cause obvious cytotoxicity directly in HSECs. Using the developed co-cultured model, further mechanism studies of retrorsine-induced HSEC damage demonstrated that the reactive pyrrolic metabolite generated by CYP-mediated bioactivation in HepaRG hepatocytes caused formation of pyrrole-protein adducts, reduction of GSH content, and generation of reactive oxygen species in HSECs, leading to cell apoptosis. The established co-culture model is reliable and applicable for cytotoxic assessment of PA-induced HSEC damage and offers a novel platform for screening toxicity of different PAs on their target cells." @default.
• W2943232094 created "2019-05-09" @default.
• W2943232094 creator A5042336604 @default.
• W2943232094 creator A5047540439 @default.
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• W2943232094 date "2019-07-01" @default.
• W2943232094 modified "2023-09-24" @default.
• W2943232094 title "Development of a two-layer transwell co-culture model for the in vitro investigation of pyrrolizidine alkaloid-induced hepatic sinusoidal damage" @default.
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• W2943232094 doi "https://doi.org/10.1016/j.fct.2019.04.057" @default.
• W2943232094 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31054999" @default.
• W2943232094 hasPublicationYear "2019" @default.
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