title: N-Acetyl cysteine does not prevent liver toxicity from chronic low-dose plus subacute high-dose paracetamol exposure in young or old mice.
abstract: Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute overexposures. The risk of hepatotoxicity from nonacute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for nonacute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and subacute paracetamol overexposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33 g/kg food) or control diet for 6 weeks. Mice were then dosed orally eight times over 3 days with additional paracetamol (250 mg/kg) or saline, followed by either one or two doses of oral NAC (1200 mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Subacute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from subacute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for subacute paracetamol toxicity.
authors.affiliation: Kolling Institute of Medical Research, Reserve Rd, St Leonards, NSW, Australia.|Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Alice Elizabeth
authors.initials: AE
authors.lastname: Kane
authors.affiliation: Kolling Institute of Medical Research, Reserve Rd, St Leonards, NSW, Australia.|Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, Australia.
authors.forename: Aniko
authors.initials: A
authors.lastname: Huizer-Pajkos
authors.affiliation: Kolling Institute of Medical Research, Reserve Rd, St Leonards, NSW, Australia.|Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Mach
authors.affiliation: Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McKenzie
authors.affiliation: National Institute on Aging, National Institutes of Health, Nathan Shock Dr, Baltimore, MD, USA.
authors.forename: Sarah Jayne
authors.initials: SJ
authors.lastname: Mitchell
authors.affiliation: National Institute on Aging, National Institutes of Health, Nathan Shock Dr, Baltimore, MD, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Kolling Institute of Medical Research, Reserve Rd, St Leonards, NSW, Australia.|Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Jones
authors.affiliation: Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.|Centre for Education and Research on Ageing and ANZAC Research Institute, Hospital Rd, Concord, NSW, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cogger
authors.affiliation: Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.|Centre for Education and Research on Ageing and ANZAC Research Institute, Hospital Rd, Concord, NSW, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.affiliation: Kolling Institute of Medical Research, Reserve Rd, St Leonards, NSW, Australia.|Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
authors.forename: Sarah Nicole
authors.initials: SN
authors.lastname: Hilmer
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000367:Age Factors; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation
chemical_list: D018712:Analgesics, Non-Narcotic; D016166:Free Radical Scavengers; D000082:Acetaminophen; D000111:Acetylcysteine
keywords: N-acetyl cysteine; ageing; chronic; hepatotoxicity; paracetamol; supratherapeutic
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