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- Title
The Effect of Aging on Acetaminophen Pharmacokinetics, Toxicity and Nrf2 in Fischer 344 Rats.
- Authors
Mach, John; Huizer-Pajkos, Aniko; Cogger, Victoria C.; McKenzie, Catriona; Le Couteur, David G.; Jones, Brett E.; de Cabo, Rafael; Hilmer, Sarah N.
- 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.
- Subjects
ACETAMINOPHEN; PHARMACOKINETICS; TOXICITY testing; LABORATORY rats; AGING; HEPATOTOXICOLOGY; BLOOD serum analysis; QUINONE compounds
- Publication
Journals of Gerontology Series A: Biological Sciences & Medical Sciences, 2014, Vol 69, Issue 4, p387
- ISSN
1079-5006
- Publication type
Article
- DOI
10.1093/gerona/glt095