Genotoxicity of paracetamol in mice and rats

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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. Pretreatment of animals with diethyl maleate enhanced the paracetamol-induced DNA SSBs, while phenobarbital and N-acetylcysteine had no marked effects. In male Wistar rats, which are more resistant to paracetamol toxicity, no increase in the level of DNA SSBs was seen in liver or kidney 4 h after exposure to 600 mg/kg paracetamol. Paracetamol (150 mg/kg and higher) inhibited DNA synthesis in B6 mice, as evidenced by a marked decrease in the incorporation of [3H]thymidine ([3H]TdR) between 15 and 75 min in the liver, spleen, intestine, bone marrow and kidney. The decrease in DNA synthesis was transient, and between 90 and 150 min the rate of radiolabel incorporated was at the control level or increased in all the organs, except the kidney. Paracetamol, at 300 mg/kg, increased the level of DNA SSBs detected in the liver, spleen and kidney of both B6 mice and Wistar rats 2 h after administration of 4-nitroquinoline N-oxide (NQO). Covalent binding of paracetamol metabolites to liver and renal DNA in diethyl maleate-pretreated mice and induction of DNA SSBs in mouse liver were observed at hepatotoxic doses of paracetamol and probably involve reactive metabolite(s) of paracetamol. These effects could be early events in the development of liver necrosis. The inhibition of (3H)TdR incorporation and the enhancement of NQO-induced DNA SSBs, on the other hand, occur at lower doses and in organs with low capacities for metabolizing paracetamol to reactive metabolite(s). These effects are most probably due to inhibition of ribonucleotide reductase by paracetamol, as previously demonstrated in vitro.

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