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Genotoxicity of paracetamol in mice and rats
J K Hongslo1, C V Smith, G Brunborg
1Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
Abstract:
The genotoxicity of paracetamol, including covalent binding to DNA, induction of DNA single-strand breaks (SSBs), and inhibition of replicative and repair synthesis of DNA, has been investigated in rodents in vivo. In the covalent binding studies male ICR mice were fasted and pretreated with diethyl maleate to deplete hepatic glutathione (GSH) and 300 mg/kg of [G-3H]paracetamol was administered intraperitoneally (i.p.). Animals were killed at 2, 6, 24, 72 and 168 h after paracetamol and hepatic or renal DNA and protein were isolated and the extent of covalent binding determined. Maximal binding to liver DNA, 8.4 +/- 3.1 pmol/mg of DNA, was observed at 2 h and declined rapidly to 2.6 pmol/mg at 24 h. Measurable binding (1.4 pmol/mg of DNA) was detected at 7 days. Protein binding in the liver in these animals peaked between 2 and 6 h (887 pmol/mg of protein at 2 h) and declined monoexponentially to 52 pmol/mg at 7 days. Although based on a limited body of data, covalent binding was also detected in DNA isolated from the kidney. DNA damage measured as SSBs by alkaline elution was induced in nuclear DNA isolated from the liver but not from the kidney, 2 h after i.p. injection of paracetamol at 600 mg/kg in male B6 mice. Only marginal DNA damage was noted at 300 mg/kg. The alkaline elution profile from damaged liver nuclei was markedly biphasic, suggesting that breaks were induced in DNA from a subpopulation of liver cells. The non-hepatotoxic paracetamol regioisomer, acetyl-m-aminophenol (600 mg/kg), which binds covalently to proteins, did not cause DNA SSBs.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Paracetamol causes genotoxicity in rodents, including DNA binding and single-strand breaks in liver cells. This damage occurs even at lower doses and is linked to paracetamol
Area of Science:
- Toxicology
- Molecular Biology
- Pharmacology
Background:
- Paracetamol (acetaminophen) is a widely used analgesic and antipyretic.
- Its genotoxicity, including DNA binding and damage, is a concern.
- Rodent models are used to investigate paracetamol's in vivo effects.
Purpose of the Study:
- To investigate the genotoxicity of paracetamol in vivo in rodents.
- To assess covalent binding of paracetamol to DNA and proteins.
- To evaluate the induction of DNA single-strand breaks (SSBs) and inhibition of DNA synthesis.
Main Methods:
- Male ICR mice were pretreated to deplete glutathione (GSH) and administered radiolabeled paracetamol.
- Hepatic and renal DNA and proteins were isolated at various time points to determine covalent binding.
- DNA damage (SSBs) was measured using alkaline elution in male B6 mice after paracetamol administration.
Main Results:
- Maximal covalent binding to liver DNA occurred at 2 hours post-administration and declined over time.
- Significant covalent binding to liver proteins was observed, peaking between 2-6 hours.
- DNA single-strand breaks were induced in liver nuclei but not kidney nuclei at 600 mg/kg paracetamol.
- The non-hepatotoxic isomer, acetyl-m-aminophenol, did not induce DNA SSBs.
Conclusions:
- Paracetamol exhibits genotoxicity in rodents, evidenced by DNA covalent binding and SSB induction in liver cells.
- The observed DNA damage suggests a potential mechanism for paracetamol-induced toxicity.
- Further research is warranted to fully elucidate the genotoxic potential and implications for human health.