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INFLAMMATION/IMMUNITY/MEDIATORS

Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

¹Veterans Administration Medical Center, White River Junction, Vermont; ²Department of Pathology, Harvard Vanguard Medical Associates, Boston, Massachusetts; ³Department of Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana; ⁴Drug Safety Evaluation, Pfizer Research and Development, Ann Arbor, Michigan; and ⁵Department of Pharmacology and Toxicology, ⁶Department of Immunology, and ⁷Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire

Submitted 25 May 2005 ; accepted in final form 16 January 2006

The objective of this study was to determine whether Toll-like receptor 4 (TLR4) has a role in alcohol-mediated acetaminophen (APAP) hepatotoxicity. TLR4 is involved in the inflammatory response to endotoxin. Others have found that ethanol-mediated liver disease is decreased in C3H/HeJ mice, which have a mutated TLR4 resulting in a decreased response to endotoxin compared with endotoxin-responsive mice. In the present study, short-term (1 wk) pretreatment with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, caused no histologically observed liver damage in either C3H/HeJ mice or endotoxin-responsive C3H/HeN mice, despite an increase in nitrotyrosine levels in the livers of C3H/HeN mice. In C3H/HeN mice pretreated with the alcohols, subsequent exposure to APAP caused a transient decrease in liver nitrotyrosine formation, possibly due to competitive interaction of peroxynitrite with APAP producing 3-nitroacetaminophen. Treatment with APAP alone resulted in steatosis in addition to congestion and necrosis in both C3H/HeN and C3H/HeJ mice, but the effects were more severe in endotoxin-responsive C3H/HeN mice. In alcohol-pretreated endotoxin-responsive C3H/HeN mice, subsequent exposure to APAP resulted in further increases in liver damage, including severe steatosis, associated with elevated plasma levels of TNF-. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-. Portal blood endotoxin levels were very low and were not detectably elevated by any of the treatments. In conclusion, this study implicates a role of TLR4 in APAP-mediated hepatotoxicity.

endotoxin; nitrotyrosine