Proteomic Identification of Potential Susceptibility Factors in Drug-Induced Liver Disease

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• 作者：Kevin D. Welch ; Bo Wen ; David R. Goodlett ; Eugene C. Yi ; Hookeun Lee ; Timothy P. Reilly ; Sidney D. Nelson ; and Lance R. Pohl
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：June 2005
• 年：2005
• 卷：18
• 期：6
• 页码：924 - 933
• 全文大小：548K
• 年卷期：v.18,no.6(June 2005)
• ISSN：1520-5010

文摘

Drug-induced liver disease (DILD) causes significant morbidity and mortality and impairsnew drug development. Currently, no known criteria can predict whether a drug will causeDILD or what risk factors make an individual susceptible. Although it has been shown inmouse studies that the disruption of key regulatory factors, such as cyclooxygenase-2 (COX-2), interleukin (IL)-6, and IL-10, increased susceptibility to DILD caused by acetaminophen(APAP), no single factor seems to be absolute. As an approach to better understand themultifactorial basis of DILD, we compared the hepatic proteome of mice that are resistant(SJL) and susceptible (C57Bl/6) to APAP-induced liver disease (AILD), using solution-basedisotope-coded affinity tag (ICAT) liquid chromatography mass spectrometry. Several novelfactors were identified that were more highly expressed in the livers of SJL mice, includingthose involved in stress response, cell proliferation and tissue regeneration, and proteinmodification, implicating these proteins as potential hepatoprotective factors. There was alsoa selective loss of several mitochondrial proteins from the livers of the susceptible C57Bl/6mice, suggesting that the loss of functional mitochondria may indeed play a role in AILD.These findings indicate that comparative hepatic proteomic analyses of susceptible and resistantmouse strains may provide a global approach for identifying potential risk factors andmechanistic pathways responsible for DILD.