title: Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type.
abstract: Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice.
authors.affiliation: Kolling Institute of Medical Research, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: alice.kane@sydney.edu.au.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Kane
authors.affiliation: National Institute on Aging, Baltimore, MD, USA. Electronic address: sarah.mitchell@nih.gov.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mitchell
authors.affiliation: Kolling Institute of Medical Research, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: jmach@uni.sydney.edu.au.
authors.forename: John
authors.initials: J
authors.lastname: Mach
authors.affiliation: Kolling Institute of Medical Research, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: aniko.huizerpajkos@health.nsw.gov.au.
authors.forename: Aniko
authors.initials: A
authors.lastname: Huizer-Pajkos
authors.affiliation: Royal Prince Alfred Hospital, Sydney, NSW, Australia. Electronic address: catriona.mckenzie@sswahs.nsw.gov.au.
authors.forename: Catriona
authors.initials: C
authors.lastname: McKenzie
authors.affiliation: Kolling Institute of Medical Research, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: bjones@med.usyd.edu.au.
authors.forename: Brett
authors.initials: B
authors.lastname: Jones
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Centre for Education and Research on Ageing, ANZAC Research Institute, Sydney, NSW, Australia. Electronic address: victoria.cogger@sydney.edu.au.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cogger
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Centre for Education and Research on Ageing, ANZAC Research Institute, Sydney, NSW, Australia. Electronic address: david.lecouteur@sydney.edu.au.
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.affiliation: National Institute on Aging, Baltimore, MD, USA. Electronic address: decabora@grc.nia.nih.gov.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Kolling Institute of Medical Research, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: sarah.hilmer@sydney.edu.au.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Hilmer
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000375:Aging / Q000473:pathology*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D018712:Analgesics, Non-Narcotic; D018836:Inflammation Mediators; D012333:RNA, Messenger; D000082:Acetaminophen
keywords: Acetaminophen; Ageing; Frailty; Hepatotoxicity; Liver; Mice; Paracetamol