Submitted on May 25, 2005
Accepted on January 16, 2006
Involvement of Toll-like Receptor 4 in Acetaminophen Hepatotoxicity
Herbert C. Yohe1*, Kimberley A. O'Hara2, Jane A. Hunt3, Tamar J. Kitzmiller3, Sheryl G. Wood3, Jenna L. Bement3, William J. Bement3, Juliana G. Szakacs4, Steven A. Wrighton5, Judith M. Jacobs6, Vsevolod Kostrubsky7, Peter R. Sinclair8, and Jacqueline F. Sinclair8
1 Veterans Administration Medical Center, White River Junction, VT, USA; Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA
2 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA
3 Veterans Administration Medical Center, White River Junction, VT, USA
4 Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
5 Drug Disposition, Lilly Research Laboratories, Indianapolis, IN, USA
6 Veterans Administration Medical Center, White River Junction, VT, USA; Department of Immunology, Dartmouth Medical School, Hanover, NH, USA
7 Drug Safety Evaluation, Pfizer R&D, Ann Arbor, MI, USA
8 Veterans Administration Medical Center, White River Junction, VT, USA; Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA; Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
* To whom correspondence should be addressed. E-mail: herbert.c.yohe{at}dartmouth.edu.
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 to endotoxin-responsive mice. In the present study, short-term (1 week) 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.
