Please use this identifier to cite or link to this item:
|Title:||Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2+/- mice: Two-stage oxidative injury|
|Keywords:||Drug-induced liver injury (DILI)|
Idiosyncratic drug toxicity
|Citation:||Lee, Y.H., Chung, M.C.M., Lin, Q., Boelsterli, U.A. (2008-08-15). Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2+/- mice: Two-stage oxidative injury. Toxicology and Applied Pharmacology 231 (1) : 43-51. ScholarBank@NUS Repository. https://doi.org/10.1016/j.taap.2008.03.025|
|Abstract:||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+/-) 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 ~ 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 β-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. © 2008 Elsevier Inc. All rights reserved.|
|Source Title:||Toxicology and Applied Pharmacology|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
There are no files associated with this item.
checked on Sep 16, 2018
WEB OF SCIENCETM
checked on Aug 14, 2018
checked on Sep 14, 2018
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.