Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.taap.2008.03.025
Title: Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2+/-mice: Two-stage oxidative injury
Authors: Lee, Y.H.
Boelsterli, U.A. 
Chung, M.C.M. 
Lin, Q. 
Keywords: Drug-induced liver injury (DILI)
Idiosyncratic drug toxicity
Mitochondria
Oxidative stress
Proteomics
Superoxide dismutase
Troglitazone
Issue Date: 2008
Source: Lee, Y.H., Boelsterli, U.A., Chung, M.C.M., Lin, Q. (2008). 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
URI: http://scholarbank.nus.edu.sg/handle/10635/28947
ISSN: 0041008X
10960333
DOI: 10.1016/j.taap.2008.03.025
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