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ToolsSaide, Katy, Sherwood, Victoria and Wheeler, Grant N. (2019) Paracetamol-induced liver injury modelled in Xenopus laevis embryos. Toxicology Letters, 302. pp. 83-91. ISSN 0378-4274
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Abstract
Introduction: Failure to predict drug-induced liver injury (DILI) remains a major contributing factor to lead compound drop-out during drug development. Xenopus embryos are amenable for early stage medium throughput small molecule screens and so have the potential to be used in pre-clinical screens. To begin to assess the usefulness and limitations of Xenopus embryos for safety assessment in the early phases of drug development, paracetamol was used as a model hepatotoxin. Paracetamol overdose is associated with acute liver injury. In mammals, the main mechanism of paracetamol-induced acute liver injury is an increased amount of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) combined with a reduction of free glutathione (GSH). Humans that have taken an overdose of paracetamol are often treated with N-acetyl cysteine (NAC). Method: Xenopus laevis embryos were treated with up to 5 mM paracetamol from stage 38 to stage 45 during development, when the liver is functional. The presence of paracetamol-induced liver injury was assessed by: (Dart et al., 2006) microRNA-122 (miR-122) expression (a hepatic marker), (Jaeschke, 2015) free GSH concentration (a marker of oxidative stress) and (Larson et al., 2005) NAC antioxidant intervention. Results: The amount of free GSH decreased significantly in embryos exposed to increasing paracetamol concentration. In embryos exposed to 5 mM paracetamol, 22.57 ± 4.25 nmol/mg GSH was detected compared to 47.11 ± 7.31 nmol/mg untreated embryos (mean ± SEM). In tail tissue, miRNA-122 expression increased 6.3-fold with 3 mM paracetamol concentration treatment compared to untreated embryos. NAC treatment altered the free GSH decline for embryos treated with up to 5 mM. Embryos exposed to 1 mM paracetamol and then exposed to 0.5 mM NAC 24 h prior to harvest, had an significantly higher amount GSH compared to embryos that were only exposed to 1 mM paracetamol (mean ± SEM; 97.1 ± 9.6 nmol/mg and 54.5 ± 6.6 nmol/mg respectively). Conclusion: Xenopus laevis embryos exhibit similar characteristics of paracetamol-induced liver injury observed in mammalian models. These data indicate that the Xenopus embryo could be a useful in vivo model to assess DILI and aid lead compound prioritisation during the early phase of drug development, in combination with pre-clinical in vitro studies. Consequently, the Xenopus embryo could contribute to the reduction principle as defined by the National Centre for the Replacement, Refinement and Reduction of Animals in Research.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | xenopus laevis,drug-induced liver injury (dili),paracetamol,pre-clinical studies |
| Faculty \ School: | Faculty of Science > School of Biological Sciences Faculty of Science > School of Pharmacy (former - to 2024) |
| UEA Research Groups: | Faculty of Science > Research Groups > Cells and Tissues Faculty of Science > Research Groups > Wheeler Group |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 02 Oct 2018 11:31 |
| Last Modified: | 24 Oct 2025 02:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/68407 |
| DOI: | 10.1016/j.toxlet.2018.09.016 |
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