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The pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice.
- Source :
-
Archives of toxicology [Arch Toxicol] 2020 Jan; Vol. 94 (1), pp. 219-229. Date of Electronic Publication: 2019 Oct 12. - Publication Year :
- 2020
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Abstract
- 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 <subscript>50</subscript> of approximately 22 µM. The cytochrome P450 (CYP)-dependency of senecionine bioactivation was confirmed in CYP reductase-deficient mice where no PA-induced hepatotoxicity was observed. Therefore, toxic metabolites of senecionine are generated by hepatic CYPs, and may be partially released from hepatocytes leading to destruction of LSECs in the pericentral region of the liver lobules. Analysis of hepatic bile salt transport by intravital two-photon imaging revealed a delayed uptake of a fluorescent bile salt analogue from the hepatic sinusoids into hepatocytes and delayed elimination. This was accompanied by transcriptional deregulation of hepatic bile salt transporters like Abcb11 or Abcc1. In conclusion, senecionine destroys LSECs although the toxic metabolite is formed in a CYP-dependent manner in the adjacent pericentral hepatocytes.
- Subjects :
- Animals
Cells, Cultured
Cholestasis pathology
Cytochrome P-450 Enzyme System genetics
Endothelial Cells drug effects
Gene Expression Regulation drug effects
Hepatocytes drug effects
Liver drug effects
Liver pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Necrosis chemically induced
Platelet Aggregation drug effects
Pyrrolizidine Alkaloids pharmacokinetics
Toxicity Tests methods
Cholestasis chemically induced
Cytochrome P-450 Enzyme System metabolism
Liver cytology
Pyrrolizidine Alkaloids toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0738
- Volume :
- 94
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Archives of toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 31606820
- Full Text :
- https://doi.org/10.1007/s00204-019-02582-8