Second exposure to acetaminophen overdose is associated with liver fibrosis in mice
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Date
2019-02-06
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Abstract
Repeated administration of hepatotoxicants is usually accompanied by liver fibrosis. However, the difference in
response as a result of repeated exposures of acetaminophen (APAP) compared to a single dose is not well-studied.
Therefore, in the current study, the liver response after a second dose of APAP was investigated. Adult fasted
Balb/C mice were exposed to two toxic doses of 300 mg/kg APAP, which were administered 72 h apart from each
other. Subsequently, blood and liver from the treated mice were collected 24 h and 72 h after both APAP administrations.
Liver transaminase, i.e. alanine amino transferase (ALT) and aspartate amino transferase (AST) levels
revealed that the fulminant liver damage was reduced after the second APAP administration compared to that
observed at the same time point after the first treatment. These results correlated with the necrotic areas as indicated
by histological analyses. Surprisingly, Picro Sirius Red (PSR) staining showed that the accumulation of extracellular
matrix after the second dose coincides with the upregulation of some fibrogenic signatures, e.g., alpha smooth
muscle actin. Non-targeted liver tissue metabolic profiling indicates that most alterations occur 24 h after the first
dose of APAP. However, the levels of most metabolites recover to basal values over time. This organ adaptation
process is also confirmed by the upregulation of antioxidative systems like e.g. superoxide dismutase and catalase.
From the results, it can be concluded that there is a different response of the liver to APAP toxic doses, if the liver
has already been exposed to APAP. A necroinflammatory process followed by a liver regeneration was observed
after the first APAP exposure. However, fibrogenesis through the accumulation of extracellular matrix is observed
after a second challenge. Therefore, further studies are required to mechanistically understand the so called “liver
memory”.
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Keywords
APAP, Metabolic profiling, Adaptation