senecionine and Cholestasis

Pyrrolizidine alkaloids (PAs) are widely occurring phytotoxins which can induce severe liver damage in humans and other mammalian species by mechanisms that are not fully understood. Therefore, we investigated the development of PA hepatotoxicity in vivo, using an acutely toxic dose of the PA senecionine in mice, in combination with intravital two-photon microscopy, histology, clinical chemistry, and in vitro experiments with primary mouse hepatocytes and liver sinusoidal endothelial cells (LSECs). We observed pericentral LSEC necrosis together with elevated sinusoidal marker proteins in the serum of senecionine-treated mice and increased sinusoidal platelet aggregation in the damaged tissue regions. In vitro experiments showed no cytotoxicity to freshly isolated LSECs up to 500 µM senecionine. However, metabolic activation of senecionine by preincubation with primary mouse hepatocytes increased the cytotoxicity to cultivated LSECs with an EC

Topics: Animals; Cells, Cultured; Cholestasis; Cytochrome P-450 Enzyme System; Endothelial Cells; Gene Expression Regulation; Hepatocytes; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Platelet Aggregation; Pyrrolizidine Alkaloids; Toxicity Tests

Topics: Animals; Cholestasis; Endothelial Cells; Liver; Mice; Pyrrolizidine Alkaloids