title: Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity.
abstract: 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.
authors.affiliation: Veterans Administration Medical Center, White River Junction, VT 05009, USA. herbert.c.yohe@dartmouth.edu
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Yohe
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: O'Hara
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hunt
authors.forename: Tamar J
authors.initials: TJ
authors.lastname: Kitzmiller
authors.forename: Sheryl G
authors.initials: SG
authors.lastname: Wood
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Bement
authors.forename: William J
authors.initials: WJ
authors.lastname: Bement
authors.forename: Juliana G
authors.initials: JG
authors.lastname: Szakacs
authors.forename: Steven A
authors.initials: SA
authors.lastname: Wrighton
authors.forename: Judith M
authors.initials: JM
authors.lastname: Jacobs
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Kostrubsky
authors.forename: Peter R
authors.initials: PR
authors.lastname: Sinclair
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Sinclair
mesh_terms: 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*
chemical_list: D018712:Analgesics, Non-Narcotic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000082:Acetaminophen; D000431:Ethanol