The Effect of Aging on Acetaminophen Pharmacokinetics, Toxicity and Nrf2 in Fischer 344 Rats

Mach, John
Huizer-Pajkos, Aniko
Cogger, Victoria C.
McKenzie, Catriona
Le Couteur, David G.
Jones, Brett E.
de Cabo, Rafael
Hilmer, Sarah N.

¹ Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Sydney, NSW, Australia.
² Departments of Clinical Pharmacology and Aged Care, Royal North Shore Hospital, Sydney, NSW, Australia.
³ Sydney Medical School, University of Sydney, NSW, Australia.
⁴ Centre for Education and Research on Aging and Anzac Research Institute, Concord Hospital and University of Sydney, NSW, Australia.
⁵ Pathology Department, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
⁶ Gastroenterology Department, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia.
⁷ Laboratory of Experimental Gerontology, National Institute on Aging, National Institute of Health, Baltimore, Maryland.

Address correspondence to Sarah Hilmer, PhD, Department of Clinical Pharmacology, Level 1, Acute services building, Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia. Email: [email protected]

Decision Editor: Placido Navas, PhD

Received February 21, 2013

Accepted May 28, 2013

Journals of Gerontology Series A: Biological Sciences and Medical Sciences 69(4):p 387-397, April 2014. | DOI: 10.1093/gerona/glt095

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.