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Title: Expression dynamics of the hepatic mitochondrial proteome of the Sod2+/- mouse in response to troglitazone administration
Authors: LEE YIE HOU
Keywords: Mitochondria, proteomics, troglitazone, drug-induced liver injury, Idiosyncratic drug toxicity
Issue Date: 2-Dec-2009
Citation: LEE YIE HOU (2009-12-02). Expression dynamics of the hepatic mitochondrial proteome of the Sod2+/- mouse in response to troglitazone administration. ScholarBank@NUS Repository.
Abstract: Idiosyncratic drug-induced liver injuries are rare adverse events that inflict susceptible patients exposed to certain normally-mild drugs. A major obstacle in understanding idiosyncratic DILI etiology includes the lack of animal models for its reproduction in the laboratory. The first aim of this study is to characterize the heterozygous Sod2+/- mouse as a surrogate model for studying DILI. Proteomic analysis on Sod2+/- liver mitochondria indicated a mild mitochondrial oxidative stress which is partly compensated by the antioxidant defense system. The results of this study are compatible with our hypothesis that the Sod2+/- mouse is a suitable animal model for studying clinically silent mitochondrial abnormalities. The second aim was to understand the dynamics of proteome changes of the Sod2+/- hepatic mitochondria treated with troglitazone, a withdrawn drug due to unacceptable hepatic liability. Proteomics analysis revealed a two-stage mitochondrial response upon short-term and long-term troglitazone administration, similar to the delayed hepatotoxicity observed in humans. Early changes involved the induction of a mitochondrial stress response. In contrast, after 4 weeks, a number of critical mitochondrial proteins were down-regulated. In addition, mitochondrial protein carbonyls and nitrotyrosine adducts were significantly increased, suggesting uncompensated oxidative damage. This integrative approach which correlated well with toxicological and histological endpoints could signify a new paradigm in predicting toxicity of idiosyncratic DILI.
Appears in Collections:Ph.D Theses (Open)

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