Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense

Hawjyh Chiu, Carol R. Gardner, Donna M. Dambach, Jennie A. Brittingham, Stephen K. Durham, Jeffrey D. Laskin, Debra L. Laskin
2003 American Journal of Physiology - Gastrointestinal and Liver Physiology  
Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense. Am J Physiol Gastrointest Liver Physiol 285: G959-G966, 2003. First published July 3, 2003 10.1152/ ajpgi.00219.2003.-Tumor necrosis factor (TNF)-␣ is a macrophage-derived proinflammatory cytokine implicated in hepatotoxicity. In the present studies, p55 TNF receptor 1 (TNFR1) Ϫ/Ϫ mice were used to assess the role of TNF-␣ in acetaminophen-induced antioxidant defense. Treatment of wild-type (WT) mice with
more » ... type (WT) mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increased serum alanine transaminases. This was correlated with a rapid depletion of hepatic glutathione (GSH). Whereas in WT mice GSH levels returned to control after 6-12 h, in TNFR1Ϫ/Ϫ mice recovery was delayed for 48 h. Delayed induction of heme oxygenase-1 and reduced expression of CuZn superoxide dismutase were also observed in TNFR1Ϫ/Ϫ compared with WT mice. This was associated with exaggerated hepatotoxicity. In WT mice, acetaminophen caused a time-dependent increase in activator protein-1 nuclear binding activity and in c-Jun expression. This response was significantly attenuated in TNFR1Ϫ/Ϫ mice. Constitutive NF-B binding activity was detectable in livers of both WT and TNFR1Ϫ/Ϫ mice. A transient decrease in this activity was observed 3 h after acetaminophen in WT mice, followed by an increase that was maximal after 6-12 h. In contrast, in TNFR1Ϫ/Ϫ mice, acetaminophen-induced decreases in NF-B activity were prolonged and did not return to control levels for 24 h. These data indicate that TNF-␣ signaling through TNFR1 plays an important role in regulating the expression of antioxidants in this model. Reduced generation of antioxidants may contribute to the increased sensitivity of TNFR1Ϫ/Ϫ mice to acetaminophen. liver; cytokines; oxidative stress; tissue injury; transcription factors ACETAMINOPHEN IS A COMMONLY used over-the-counter analgesic and antipyretic agent. When ingested in excess quantities, acetaminophen is metabolized by cytochrome P-450 to N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive and toxic metabolite. Cova-
doi:10.1152/ajpgi.00219.2003 pmid:12842828 fatcat:ncenh7jbyzeixiiqatvreoq2gm