PMID- 22396533
OWN - NLM
STAT- MEDLINE
DCOM- 20120730
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 19
DP  - 2012 May 4
TI  - Additive effects of mitochondrion-targeted cytochrome CYP2E1 and alcohol toxicity 
      on cytochrome c oxidase function and stability of respirosome complexes.
PG  - 15284-97
LID - 10.1074/jbc.M111.314062 [doi]
AB  - Alcohol treatment induces oxidative stress by a combination of increased 
      production of partially reduced oxygen species and decreased cellular antioxidant 
      pool, including GSH. Recently, we showed that mitochondrion-targeted CYP2E1 
      augments alcohol-mediated toxicity, causing an increase in reactive oxygen 
      species production and oxidative stress. Here, we show that cytochrome c oxidase 
      (CcO), the terminal oxidase of the mitochondrial respiratory chain, is a critical 
      target of CYP2E1-mediated alcohol toxicity. COS-7 and Hep G2 cell lines 
      expressing predominantly mitochondrion-targeted (Mt(++)) CYP2E1 and livers from 
      alcohol-treated rats showed loss of CcO activity and increased protein 
      carbonylation, which was accompanied by a decline in the steady state levels of 
      subunits I, IVI1, and Vb of the CcO complex. This was also accompanied by reduced 
      mitochondrial DNA content and reduced mitochondrial mRNA. These changes were more 
      prominent in Mt(++) cells in comparison with wild type (WT) CYP2E1-expressing or 
      ER(+) (mostly microsome-targeted) cells. In addition, mitochondrion-specific 
      antioxidants, ubiquinol conjugated to triphenyl phosphonium, triphenylphosphonium 
      conjugated carboxyl proxyl, and the CYP2E1 inhibitor diallyl sulfide prevented 
      the loss of CcO activity and the CcO subunits, most likely through reduced 
      oxidative damage to the enzyme complex. Our results suggest that damage to CcO 
      and dissociation of respirosome complexes are critical factors in alcohol-induced 
      toxicity, which is augmented by mitochondrion-targeted CYP2E1. We propose that 
      CcO is one of the direct and immediate targets of alcohol-induced toxicity 
      causing respiratory dysfunction.
FAU - Bansal, Seema
AU  - Bansal S
AD  - Department of Animal Biology and the Mari Lowe Center for Comparative Oncology, 
      School of Veterinary Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Srinivasan, Satish
AU  - Srinivasan S
FAU - Anandasadagopan, Sureshkumar
AU  - Anandasadagopan S
FAU - Chowdhury, Anindya Roy
AU  - Chowdhury AR
FAU - Selvaraj, Venkatesh
AU  - Selvaraj V
FAU - Kalyanaraman, Balaraman
AU  - Kalyanaraman B
FAU - Joseph, Joy
AU  - Joseph J
FAU - Avadhani, Narayan G
AU  - Avadhani NG
LA  - eng
GR  - R01 AA017749/AA/NIAAA NIH HHS/United States
GR  - R01 GM034883/GM/NIGMS NIH HHS/United States
GR  - AA-017749/AA/NIAAA NIH HHS/United States
GR  - GM-34883/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, American Recovery and Reinvestment Act
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120306
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antioxidants)
RN  - 0 (Central Nervous System Depressants)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 3K9958V90M (Ethanol)
RN  - EC 1.14.13.- (Cytochrome P-450 CYP2E1)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - COS Cells
MH  - Central Nervous System Depressants/toxicity
MH  - Chlorocebus aethiops
MH  - Cytochrome P-450 CYP2E1/*metabolism
MH  - DNA, Mitochondrial/genetics/metabolism
MH  - Electron Transport/*drug effects
MH  - Electron Transport Complex IV/genetics/*metabolism
MH  - Ethanol/*toxicity
MH  - Hep G2 Cells
MH  - Humans
MH  - Immunoblotting
MH  - Liver/drug effects/metabolism/pathology
MH  - Microsomes/drug effects/metabolism
MH  - Mitochondria/*drug effects/genetics/metabolism
MH  - Mitochondria, Liver/drug effects/genetics/metabolism
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Oxygen Consumption/drug effects
MH  - Protein Carbonylation/drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transcription, Genetic/drug effects
PMC - PMC3346148
EDAT- 2012/03/08 06:00
MHDA- 2012/07/31 06:00
PMCR- 2013/05/04
CRDT- 2012/03/08 06:00
PHST- 2012/03/08 06:00 [entrez]
PHST- 2012/03/08 06:00 [pubmed]
PHST- 2012/07/31 06:00 [medline]
PHST- 2013/05/04 00:00 [pmc-release]
AID - S0021-9258(20)46179-4 [pii]
AID - M111.314062 [pii]
AID - 10.1074/jbc.M111.314062 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 May 4;287(19):15284-97. doi: 10.1074/jbc.M111.314062. Epub 2012 
      Mar 6.