Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity.
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-alpha. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-alpha. 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.
Yohe
Herbert C
HC
Veterans Administration Medical Center, White River Junction, VT 05009, USA. herbert.c.yohe@dartmouth.edu
O'Hara
Kimberley A
KA
Hunt
Jane A
JA
Kitzmiller
Tamar J
TJ
Wood
Sheryl G
SG
Bement
Jenna L
JL
Bement
William J
WJ
Szakacs
Juliana G
JG
Wrighton
Steven A
SA
Jacobs
Judith M
JM
Kostrubsky
Vsevolod
V
Sinclair
Peter R
PR
Sinclair
Jacqueline F
JF
D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000818:Animals; D004357:Drug Synergism; D000431:Ethanol / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000082:Acetaminophen; D000431:Ethanol