Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice

Journal Article · Sun Jan 15 04:00:00 EST 2006 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2005.10.001· OSTI ID:20783414

Tolson, J Keith; Dix, David J ^[1]; Voellmy, Richard W ^[2]; Roberts, Stephen M ^[3]

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1. Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27709 (United States)
2. Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33124 (United States)
3. J. Hillis Miller Health Science Center, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32611 (United States) and J. Hillis Miller Health Science Center, Department of Physiological Sciences, University of Florida, Gainesville, FL 32611 (United States)

The effect of the inducible forms of 70 kDa heat shock protein (Hsp70i) on acetaminophen (APAP) hepatotoxicity was assessed in an Hsp70i knockout mouse model. Absence of the Hsp70i protein in liver was verified by monitoring Hsp levels in knockout and control mice after heat stress (41.5 {sup o}C water bath immersion for 30 min). Hsp70i knockout mice were more susceptible to APAP-induced hepatotoxicity than controls, as indicated by elevated serum alanine aminotransferase activities 24 and 48 h after the APAP dose. Increased APAP hepatotoxicity in knockout mice was verified by morphological evaluation of liver sections. The difference in toxic response to APAP between knockout and control strain mice could not be attributed to differences in APAP bioactivation, assessed by measurement of CYP2E1 and glutathione S-transferase activities, hepatic nonprotein sulfhydryl content, or covalent binding of reactive APAP metabolites to proteins. Pretreatment with transient hyperthermia to produce a general upregulation of Hsps resulted in decreased APAP hepatotoxicity in both the knockout and control strains. Among thermally-pretreated mice, hepatotoxicity of APAP was greater in the knockouts compared with the control strain. These observations suggest that increased Hsp70i expression in response to APAP acts to limit the extent of tissue injury. Results further suggest that other factors related to heat stress can also contribute to protection against APAP toxicity.

• OSTI ID: 20783414
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1-2 Vol. 210; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
BIOLOGICAL STRESS
GLUTATHIONE
HEAT STRESS
HEAT-SHOCK PROTEINS
HYPERTHERMIA
INJURIES
LIVER
METABOLITES
MICE
TOXICITY