PMID- 20100502
OWN - NLM
STAT- MEDLINE
DCOM- 20100603
LR  - 20211020
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 245
IP  - 1
DP  - 2010 May 15
TI  - Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity.
PG  - 36-46
LID - 10.1016/j.taap.2010.01.008 [doi]
AB  - Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate 
      intracellular compartmentalization of various signaling molecules. In the present 
      studies, transgenic mice with a targeted disruption of the Cav-1 gene 
      (Cav-1(-/-)) were used to assess the role of Cav-1 in acetaminophen-induced 
      hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) 
      resulted in centrilobular hepatic necrosis and increases in serum transaminases. 
      This was correlated with decreased expression of Cav-1 in the liver. 
      Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1(-/-) 
      mice, an effect that was independent of acetaminophen metabolism. Acetaminophen 
      administration resulted in increased hepatic expression of the oxidative stress 
      marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and 
      superoxide dismutase-1; no differences were noted between the genotypes 
      suggesting that reduced toxicity in Cav-1(-/-) mice is not due to alterations in 
      antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression 
      of the pro-inflammatory cytokines, interleukin-1beta, and monocyte 
      chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 
      15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. 
      Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in 
      Cav-1(-/-) mice. Although expression of tumor necrosis factor-alpha, a potent 
      hepatocyte mitogen, was up-regulated in the liver of Cav-1(-/-) mice after 
      acetaminophen, expression of proliferating cell nuclear antigen and survivin, 
      markers of cellular proliferation, were delayed, which may reflect the reduced 
      need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a 
      role in promoting inflammation and toxicity during the pathogenesis of 
      acetaminophen-induced injury.
FAU - Gardner, Carol R
AU  - Gardner CR
AD  - Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario 
      School of Pharmacy, Piscataway, NJ 08854, USA. cgardner@eohsi.rutgers.edu
FAU - Gray, Joshua P
AU  - Gray JP
FAU - Joseph, Laurie B
AU  - Joseph LB
FAU - Cervelli, Jessica
AU  - Cervelli J
FAU - Bremer, Nicole
AU  - Bremer N
FAU - Kim, Yunjung
AU  - Kim Y
FAU - Mishin, Vladimir
AU  - Mishin V
FAU - Laskin, Jeffrey D
AU  - Laskin JD
FAU - Laskin, Debra L
AU  - Laskin DL
LA  - eng
GR  - U54 AR055073-03/AR/NIAMS NIH HHS/United States
GR  - P30 ES005022-209008/ES/NIEHS NIH HHS/United States
GR  - AR055073/AR/NIAMS NIH HHS/United States
GR  - R01 CA132624-02/CA/NCI NIH HHS/United States
GR  - U54 AR055073-04/AR/NIAMS NIH HHS/United States
GR  - R01 GM034310-20/GM/NIGMS NIH HHS/United States
GR  - P30 ES005022/ES/NIEHS NIH HHS/United States
GR  - P30 ES005022-199008/ES/NIEHS NIH HHS/United States
GR  - U54 AR055073/AR/NIAMS NIH HHS/United States
GR  - R01 CA132624-01/CA/NCI NIH HHS/United States
GR  - R01 GM034310-22/GM/NIGMS NIH HHS/United States
GR  - ES005022/ES/NIEHS NIH HHS/United States
GR  - GM034310/GM/NIGMS NIH HHS/United States
GR  - CA132634/CA/NCI NIH HHS/United States
GR  - R01 ES004738/ES/NIEHS NIH HHS/United States
GR  - R01 ES004738-15/ES/NIEHS NIH HHS/United States
GR  - R01 CA132624/CA/NCI NIH HHS/United States
GR  - R01 ES004738-16A2/ES/NIEHS NIH HHS/United States
GR  - R01 GM034310-24/GM/NIGMS NIH HHS/United States
GR  - R01 ES004738-17/ES/NIEHS NIH HHS/United States
GR  - R01 GM034310-21A1/GM/NIGMS NIH HHS/United States
GR  - R01 GM034310/GM/NIGMS NIH HHS/United States
GR  - ES004738/ES/NIEHS NIH HHS/United States
GR  - R01 GM034310-23/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20100125
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Antioxidants)
RN  - 0 (Caveolin 1)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-1)
RN  - 130068-27-8 (Interleukin-10)
RN  - 362O9ITL9D (Acetaminophen)
SB  - IM
MH  - Acetaminophen/*toxicity
MH  - Animals
MH  - Antioxidants/metabolism
MH  - Caveolin 1/genetics/*physiology
MH  - Cell Proliferation/drug effects
MH  - Chemokine CCL2/metabolism
MH  - Inflammation/metabolism
MH  - Inflammation Mediators/metabolism
MH  - Interleukin-1/metabolism
MH  - Interleukin-10/metabolism
MH  - Liver/*drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
PMC - PMC2862893
MID - NIHMS173077
COIS- Conflict of interest statement: The authors declare that is are no conflicts of 
      interest.
EDAT- 2010/01/27 06:00
MHDA- 2010/06/04 06:00
PMCR- 2011/05/15
CRDT- 2010/01/27 06:00
PHST- 2009/12/22 00:00 [received]
PHST- 2010/01/13 00:00 [revised]
PHST- 2010/01/14 00:00 [accepted]
PHST- 2010/01/27 06:00 [entrez]
PHST- 2010/01/27 06:00 [pubmed]
PHST- 2010/06/04 06:00 [medline]
PHST- 2011/05/15 00:00 [pmc-release]
AID - S0041-008X(10)00019-0 [pii]
AID - 10.1016/j.taap.2010.01.008 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2010 May 15;245(1):36-46. doi: 
      10.1016/j.taap.2010.01.008. Epub 2010 Jan 25.