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

Drug-induced liver disease (DILD) causes significant morbidity and mortality and impairs
new drug development. Currently, no known criteria can predict whether a drug will cause
DILD or what risk factors make an individual susceptible. Although it has been shown in
mouse 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 the
multifactorial 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-based
isotope-coded affinity tag (ICAT) liquid chromatography mass spectrometry. Several novel
factors were identified that were more highly expressed in the livers of SJL mice, including
those involved in stress response, cell proliferation and tissue regeneration, and protein
modification, implicating these proteins as potential hepatoprotective factors. There was also
a selective loss of several mitochondrial proteins from the livers of the susceptible C57Bl/6
mice, 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 resistant
mouse strains may provide a global approach for identifying potential risk factors and
mechanistic pathways responsible for DILD.