Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2{sup +/-} mice: Two-stage oxidative injury
Journal Article
·
· Toxicology and Applied Pharmacology
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597 (Singapore)
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597 (Singapore)
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543 (Singapore)
The determinants of susceptibility to troglitazone-induced idiosyncratic liver injury have not yet been determined; however, troglitazone has been shown to target mitochondria and induce mitochondria-mediated hepatocellular injury in vitro. The aim of this study was to use a systems approach to analyze the dynamics of mitochondrial changes at the proteome level and more clearly define the mechanisms and time course of troglitazone hepatotoxicity by using a previously characterized mouse model that is highly sensitized to troglitazone hepatotoxicity. Mice heterozygous in mitochondrial superoxide dismutase-2 (Sod2{sup +/-}) were injected intraperitoneally with troglitazone (30 mg/kg/day) or vehicle daily for 2 or 4 weeks. Hepatic mitochondria were isolated, purified, and subjected to two-dimensional difference gel electrophoresis (2D-DIGE). We found that among the {approx} 1500 resolved hepatic mitochondrial proteins, 70 exhibited significantly altered abundance after troglitazone treatment. MALDI-TOF/TOF MS/MS analysis revealed that early changes (2 weeks) included increased levels of heat shock protein family members (mortalin, HSP7C), Lon protease, and catalase, indicating induction of a mitochondrial stress response. In contrast, after 4 weeks, a number of critical proteins including ATP synthase {beta}-subunit, aconitase-2, and catalase exhibited decreased abundance, and total protein carbonyls were significantly increased, suggesting uncompensated oxidative damage. Aconitase-2 (ACO2) was decreased at both time points, making this protein a potential sensitive and early biomarker for mitochondrial oxidant stress. These results show that, in this murine model of underlying clinically silent mitochondrial stress, superimposed troglitazone induces a two-stage response: an initial adaptive response, followed by a toxic response involving oxidant injury to mitochondrial proteins.
- OSTI ID:
- 21140925
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 231; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity
Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition
The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity
Journal Article
·
Wed Jul 15 00:00:00 EDT 2009
· Toxicology and Applied Pharmacology
·
OSTI ID:21272602
Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition
Journal Article
·
Mon Nov 01 00:00:00 EDT 2010
· Toxicology and Applied Pharmacology
·
OSTI ID:21451193
The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity
Journal Article
·
Tue Mar 15 00:00:00 EDT 2011
· Toxicology and Applied Pharmacology
·
OSTI ID:21535260