PMID- 16081117
OWN - NLM
STAT- MEDLINE
DCOM- 20060419
LR  - 20161124
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 211
IP  - 2
DP  - 2006 Mar 1
TI  - Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced 
      inflammatory mediator production and hepatotoxicity.
PG  - 157-65
AB  - Oxidative stress plays an important role in acetaminophen (APAP)-induced 
      hepatotoxicity. In addition to inducing direct cellular damage, oxidants can 
      activate transcription factors including NF-kappaB, which regulate the production 
      of inflammatory mediators implicated in hepatotoxicity. Here, we investigated the 
      role of APAP-induced oxidative stress and NF-kappaB in inflammatory mediator 
      production. Treatment of mice with APAP (300 mg/kg, i.p.) resulted in 
      centrilobular hepatic necrosis and increased serum aminotransferase levels. This 
      was correlated with depletion of hepatic glutathione and CuZn superoxide 
      dismutase (SOD). APAP administration also increased expression of the 
      proinflammatory mediators, interleukin-1beta (IL-1beta), tumor necrosis 
      factor-alpha (TNFalpha), macrophage chemotactic protein-1 (MCP-1), and KC/gro, 
      and the anti-inflammatory cytokine, interleukin-10 (IL-10). Pretreatment of mice 
      with the antioxidant, N-acetylcysteine (NAC) prevented APAP-induced depletion of 
      glutathione and CuZnSOD, as well as hepatotoxicity. NAC also abrogated 
      APAP-induced increases in TNFalpha, KC/gro, and IL-10, but augmented expression 
      of the anti-inflammatory cytokines interleukin-4 (IL-4) and transforming growth 
      factor-beta (TGFbeta). No effects were observed on IL-1beta or MCP-1 expression. 
      To determine if NF-kappaB plays a role in regulating mediator production, we used 
      transgenic mice with a targeted disruption of the gene for NF-kappaB p50. As 
      observed with NAC pretreatment, the loss of NF-kappaB p50 was associated with 
      decreased ability of APAP to upregulate TNFalpha, KC/gro, and IL-10 expression 
      and increased expression of IL-4 and TGFbeta. However, in contrast to NAC 
      pretreatment, the loss of p50 had no effect on APAP-induced hepatotoxicity. These 
      data demonstrate that APAP-induced cytokine expression in the liver is influenced 
      by oxidative stress and that this is dependent, in part, on NF-kappaB. However, 
      NF-kappaB p50-dependent responses do not appear to play a major role in the 
      pathogenesis of toxicity in this model.
FAU - Dambach, Donna M
AU  - Dambach DM
AD  - Department of Pharmacology and Toxicology, Rutgers University, 160 Frelinghuysen 
      Road, Piscataway, NJ 08854, USA.
FAU - Durham, Stephen K
AU  - Durham SK
FAU - Laskin, Jeffrey D
AU  - Laskin JD
FAU - Laskin, Debra L
AU  - Laskin DL
LA  - eng
GR  - CA100994/CA/NCI NIH HHS/United States
GR  - ES004738/ES/NIEHS NIH HHS/United States
GR  - ES005022/ES/NIEHS NIH HHS/United States
GR  - GM034310/GM/NIGMS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20050802
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Analgesics, Non-Narcotic)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-1)
RN  - 0 (Macrophage Inflammatory Proteins)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
RN  - 207137-56-2 (Interleukin-4)
RN  - 362O9ITL9D (Acetaminophen)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 2.6.1.2 (Alanine Transaminase)
RN  - GAN16C9B8O (Glutathione)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetaminophen/administration & dosage/*toxicity
MH  - Acetylcysteine/pharmacology
MH  - Alanine Transaminase/blood
MH  - Analgesics, Non-Narcotic/administration & dosage/toxicity
MH  - Animals
MH  - Blotting, Western
MH  - Chemical and Drug Induced Liver Injury/*etiology/metabolism/pathology
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Chemokines/genetics/metabolism
MH  - Gene Expression/drug effects
MH  - Glutathione/metabolism
MH  - Humans
MH  - Inflammation Mediators/*metabolism
MH  - Injections, Intraperitoneal
MH  - Interleukin-1/biosynthesis/genetics
MH  - Interleukin-10/biosynthesis/genetics
MH  - Interleukin-4/genetics/metabolism
MH  - Liver/chemistry/drug effects/metabolism
MH  - Macrophage Inflammatory Proteins/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred Strains
MH  - Mice, Knockout
MH  - NF-kappa B p50 Subunit/genetics/*physiology
MH  - Necrosis/chemically induced/pathology
MH  - Oxidative Stress
MH  - RNA, Messenger/drug effects/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Superoxide Dismutase/metabolism
MH  - Time Factors
MH  - Transcription Factors/genetics/metabolism
MH  - Transforming Growth Factor beta/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/metabolism
EDAT- 2005/08/06 09:00
MHDA- 2006/04/20 09:00
CRDT- 2005/08/06 09:00
PHST- 2005/05/11 00:00 [received]
PHST- 2005/06/22 00:00 [revised]
PHST- 2005/06/23 00:00 [accepted]
PHST- 2005/08/06 09:00 [pubmed]
PHST- 2006/04/20 09:00 [medline]
PHST- 2005/08/06 09:00 [entrez]
AID - S0041-008X(05)00398-4 [pii]
AID - 10.1016/j.taap.2005.06.024 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2006 Mar 1;211(2):157-65. doi: 
      10.1016/j.taap.2005.06.024. Epub 2005 Aug 2.