PMID- 19632256
OWN - NLM
STAT- MEDLINE
DCOM- 20091026
LR  - 20211020
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 240
IP  - 3
DP  - 2009 Nov 1
TI  - Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces 
      mitochondrial dysfunction and cell death in human hepatocytes.
PG  - 348-54
LID - 10.1016/j.taap.2009.07.021 [doi]
AB  - Thiazolidinediones (TZDs), such as troglitazone (TRO) and rosiglitazone (ROSI), 
      improve insulin resistance by acting as ligands for the nuclear receptor 
      peroxisome proliferator-activated receptor-gamma (PPARgamma). TRO was withdrawn 
      from the market because of reports of serious hepatotoxicity. A growing body of 
      evidence suggests that TRO caused mitochondrial dysfunction and induction of 
      apoptosis in human hepatocytes but its mechanisms of action remain unclear. We 
      hypothesized that damage to mitochondrial DNA (mtDNA) is an initiating event 
      involved in TRO-induced mitochondrial dysfunction and hepatotoxicity. Primary 
      human hepatocytes were exposed to TRO and ROSI. The results obtained revealed 
      that TRO, but not ROSI at equimolar concentrations, caused a substantial increase 
      in mtDNA damage and decreased ATP production and cellular viability. The reactive 
      oxygen species (ROS) scavenger, N-acetyl cystein (NAC), significantly diminished 
      the TRO-induced cytotoxicity, suggesting involvement of ROS in TRO-induced 
      hepatocyte cytotoxicity. The PPARgamma antagonist (GW9662) did not block the 
      TRO-induced decrease in cell viability, indicating that the TRO-induced 
      hepatotoxicity is PPARgamma-independent. Furthermore, TRO induced hepatocyte 
      apoptosis, caspase-3 cleavage and cytochrome c release. Targeting of a DNA repair 
      protein to mitochondria by protein transduction using a fusion protein containing 
      the DNA repair enzyme Endonuclease III (EndoIII) from Escherichia coli, a 
      mitochondrial translocation sequence (MTS) and the protein transduction domain 
      (PTD) from HIV-1 TAT protein protected hepatocytes against TRO-induced toxicity. 
      Overall, our results indicate that significant mtDNA damage caused by TRO is a 
      prime initiator of the hepatoxicity caused by this drug.
FAU - Rachek, Lyudmila I
AU  - Rachek LI
AD  - Department of Cell Biology and Neuroscience, College of Medicine, University of 
      South Alabama, Mobile, AL 36688, USA. lrachek@jaguar1.usouthal.edu
FAU - Yuzefovych, Larysa V
AU  - Yuzefovych LV
FAU - Ledoux, Susan P
AU  - Ledoux SP
FAU - Julie, Neil L
AU  - Julie NL
FAU - Wilson, Glenn L
AU  - Wilson GL
LA  - eng
GR  - R01 ES005865-14/ES/NIEHS NIH HHS/United States
GR  - DK073808/DK/NIDDK NIH HHS/United States
GR  - R01 ES003456-21/ES/NIEHS NIH HHS/United States
GR  - R01 DK073808/DK/NIDDK NIH HHS/United States
GR  - R01 DK073808-03/DK/NIDDK NIH HHS/United States
GR  - R01 DK073808-02/DK/NIDDK NIH HHS/United States
GR  - R01 DK073808-01A2/DK/NIDDK NIH HHS/United States
GR  - ES05865/ES/NIEHS NIH HHS/United States
GR  - R01 ES005865-15/ES/NIEHS NIH HHS/United States
GR  - R01 ES003456-22A2/ES/NIEHS NIH HHS/United States
GR  - R01 ES003456/ES/NIEHS NIH HHS/United States
GR  - R01 ES005865-16/ES/NIEHS NIH HHS/United States
GR  - F32 ES005865/ES/NIEHS NIH HHS/United States
GR  - R01 ES003456-23/ES/NIEHS NIH HHS/United States
GR  - R01 ES005865-13/ES/NIEHS NIH HHS/United States
GR  - R01 ES003456-20/ES/NIEHS NIH HHS/United States
GR  - R01 DK073808-02S1/DK/NIDDK NIH HHS/United States
GR  - R01 ES005865/ES/NIEHS NIH HHS/United States
GR  - ES03456/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090724
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Chromans)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PPAR gamma)
RN  - 0 (Thiazolidinediones)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - I66ZZ0ZN0E (Troglitazone)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Apoptosis/*drug effects
MH  - Cells, Cultured
MH  - Chromans/*pharmacology
MH  - *DNA Damage
MH  - DNA, Mitochondrial/*drug effects/physiology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Hepatocytes/cytology/*drug effects/metabolism
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - PPAR gamma/antagonists & inhibitors
MH  - Rosiglitazone
MH  - Thiazolidinediones/*pharmacology
MH  - Troglitazone
PMC - PMC2767118
MID - NIHMS135196
EDAT- 2009/07/28 09:00
MHDA- 2009/10/27 06:00
PMCR- 2010/11/01
CRDT- 2009/07/28 09:00
PHST- 2008/12/09 00:00 [received]
PHST- 2009/06/29 00:00 [revised]
PHST- 2009/07/14 00:00 [accepted]
PHST- 2009/07/28 09:00 [entrez]
PHST- 2009/07/28 09:00 [pubmed]
PHST- 2009/10/27 06:00 [medline]
PHST- 2010/11/01 00:00 [pmc-release]
AID - S0041-008X(09)00294-4 [pii]
AID - 10.1016/j.taap.2009.07.021 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2009 Nov 1;240(3):348-54. doi: 
      10.1016/j.taap.2009.07.021. Epub 2009 Jul 24.