PMID- 23697945
OWN - NLM
STAT- MEDLINE
DCOM- 20150115
LR  - 20220310
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 26
IP  - 7
DP  - 2013 Jul 15
TI  - Disruption of thioredoxin reductase 1 protects mice from acute 
      acetaminophen-induced hepatotoxicity through enhanced NRF2 activity.
PG  - 1088-96
LID - 10.1021/tx4001013 [doi]
AB  - The critical importance of glutathione in mitigating the deleterious effects of 
      electrophile generating drugs such as acetaminophen (APAP) is well established. 
      However, the role of other antioxidant systems, such as that provided by 
      thioredoxin, has not been extensively studied. Selenoprotein thioredoxin 
      reductase 1 (Txnrd1) is important for attenuating activation of the apoptosis 
      signaling-regulating kinase 1 (ASK1) and the c-Jun N-terminal kinase (JNK) 
      pathway caused by high doses of APAP. Therefore, a detailed investigation of the 
      role of Txnrd1 in APAP-induced hepatotoxicity was conducted. Liver-specific 
      Txnrd1 knockout mice (Txnrd1(DeltaLiv)) were generated and treated with a hepatotoxic 
      dose (400 mg/kg) of APAP for 1 or 6 h. Liver toxicity was assessed by measuring 
      the activities of liver enzymes aspartate aminotransferase and alanine 
      aminotransferase in serum, in addition to histopathological analysis of liver 
      sections and analysis of glutathione levels. At 1 h post-APAP treatment, total 
      and mitochondrial glutathione levels in control and Txnrd1(DeltaLiv) mice were 
      similarly depleted. However, at 6 h post-APAP treatment, Txnrd1(DeltaLiv) mice were 
      resistant to APAP toxicity as liver enzymes and histology were not significantly 
      different from the corresponding untreated mice. Analyses revealed the 
      compensatory up-regulation of many of the nuclear factor erythroid 2-related 
      factor 2 (NRF2) target genes and proteins in Txnrd1(DeltaLiv) mice with and without 
      APAP treatment. Yet, JNK was phosphorylated to a similar extent in APAP-treated 
      control mice. The results suggest that Txnrd1(DeltaLiv) mice are primed for 
      xenobiotic detoxication primarily through NRF2 activation.
FAU - Patterson, Andrew D
AU  - Patterson AD
AD  - Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, 
      National Institutes of Health , Bethesda, Maryland 20892, United States.
FAU - Carlson, Bradley A
AU  - Carlson BA
FAU - Li, Fei
AU  - Li F
FAU - Bonzo, Jessica A
AU  - Bonzo JA
FAU - Yoo, Min-Hyuk
AU  - Yoo MH
FAU - Krausz, Kristopher W
AU  - Krausz KW
FAU - Conrad, Marcus
AU  - Conrad M
FAU - Chen, Chi
AU  - Chen C
FAU - Gonzalez, Frank J
AU  - Gonzalez FJ
FAU - Hatfield, Dolph L
AU  - Hatfield DL
LA  - eng
GR  - Z01 BC005561-20/ImNIH/Intramural NIH HHS/United States
GR  - Z01 BC005561-21/ImNIH/Intramural NIH HHS/United States
GR  - Z01 BC005562-20/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20130607
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 362O9ITL9D (Acetaminophen)
RN  - EC 1.8.1.9 (Thioredoxin Reductase 1)
RN  - EC 1.8.1.9 (Txnrd1 protein, mouse)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Acetaminophen/*toxicity
MH  - Animals
MH  - Chemical and Drug Induced Liver Injury/*metabolism/pathology/*prevention & 
      control
MH  - Glutathione/analysis
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Thioredoxin Reductase 1/*antagonists & inhibitors/deficiency/metabolism
PMC - PMC6334300
MID - NIHMS1000650
COIS- The authors declare no competing financial interest.
EDAT- 2013/05/24 06:00
MHDA- 2015/01/16 06:00
PMCR- 2019/01/16
CRDT- 2013/05/24 06:00
PHST- 2013/05/24 06:00 [entrez]
PHST- 2013/05/24 06:00 [pubmed]
PHST- 2015/01/16 06:00 [medline]
PHST- 2019/01/16 00:00 [pmc-release]
AID - 10.1021/tx4001013 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2013 Jul 15;26(7):1088-96. doi: 10.1021/tx4001013. Epub 2013 
      Jun 7.