title: The effect of aging on acetaminophen pharmacokinetics, toxicity and Nrf2 in Fischer 344 rats.
abstract: We investigated the effect of aging on hepatic pharmacokinetics and the degree of hepatotoxicity following a toxic dose of acetaminophen. Young and old male Fischer 344 rats were treated with 800 mg/kg acetaminophen (young n = 8, old n = 5) or saline (young n = 9, old n = 9). Serum measurements showed old rats treated with acetaminophen had significantly lower serum alanine aminotransferase and higher acetaminophen and acetaminophen glucuronide levels and creatinine, compared with acetaminophen treated young rats (p < .05). Immunoblotting and activity assays showed old saline-treated rats had twofold lower cytochrome P450 2E1 activity and threefold higher NAD(P)H quinone oxireductase 1 protein expression and activity than young saline-treated rats (p < .05), although Nrf2, glutathione cysteine ligase-modulatory subunit, glutathione cysteine ligase-catalytic subunit, and cytochrome P450 2E1 protein expressions were unchanged. Primary hepatocytes isolated from young rats treated with 10 mM acetaminophen had lower survival than those from old rats (52.4% ± 5.8%, young; 83.6% ± 1.7%, old, p < .05). The pharmacokinetic changes described may decrease susceptibility to acetaminophen-induced hepatotoxicity but may increase risk of nephrotoxicity in old age.
authors.affiliation: Department of Clinical Pharmacology, Level 1, Acute services building, Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia. sarah.hilmer@sydney.edu.au.
authors.forename: John
authors.initials: J
authors.lastname: Mach
authors.forename: Aniko
authors.initials: A
authors.lastname: Huizer-Pajkos
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.forename: Catriona
authors.initials: C
authors.lastname: McKenzie
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.forename: Brett E
authors.initials: BE
authors.lastname: Jones
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Hilmer
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018712:Analgesics, Non-Narcotic; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000082:Acetaminophen; C037386:acetaminophen glucuronide
keywords: Acetaminophen; Aging; Pharmacokinetics.; Toxicity