Genotoxicity of paracetamol in mice and rats.
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)
Hongslo
J K
JK
Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
Smith
C V
CV
Brunborg
G
G
Søderlund
E J
EJ
Holme
J A
JA
D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004357:Drug Synergism; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009153:Mutagens / Q000633:toxicity*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D008298:Maleates; D009153:Mutagens; D000082:Acetaminophen; D015112:4-Nitroquinoline-1-oxide; D004247:DNA; C014476:diethyl maleate