Genomic Identification of Potential Risk Factors during Acetaminophen-Induced Liver Disease in Susceptible and Resistant Strains of Mice

Drug-induced liver disease (DILD) continues to cause significant morbidity and mortality and impair
new drug development. Mounting evidence suggests that DILD is a complex, multifactorial disease in
which no one factor is likely to be an absolute indicator of susceptibility. As an approach to better
understand the multifactorial basis of DILD, we recently compared the hepatic proteomes of mice that
were resistant (SJL) and susceptible (C57Bl/6) to APAP-induced liver disease (AILD) wherein we identified
potential risk factors and mechanistic pathways responsible for DILD. In this study, we have uncovered
additional potential risk factors by comparing hepatic mRNA expression profiles of the same two strains
of mice with that of SJLxB6-F1 hybrid (F1) mice, which were found to be of intermediate susceptibility
to AILD. Global hepatic gene expression profiling over a 24 h period following APAP treatment revealed
elevated patterns in the mRNA expression of cytoprotective genes in resistant SJL mice as compared to
susceptible B6 mice, while F1 mice had intermediate mRNA expression levels of these genes. One of
these genes encoded for heat shock protein (HSP) 70 whose relative protein expression among the three
strains of mice was found to parallel that of their mRNA levels, suggesting that this protein had a protective
role against AILD. However, there was no difference in the susceptibility of HSP70 knockout (KO)
mice to AILD as compared to wild-type (WT) mice. There were also protoxicant genes, such as osteopontin
(OPN), with elevated mRNA expression levels in the B6 mice as compared to the SJL mice and with
intermediate levels in the F1 mice, suggesting that they may play a role in exacerbating liver injury after
APAP treatment. In support of this hypothesis, OPN KO mice were found to be more resistant to AILD
than WT mice. Additionally, the results from both the proteomic and the genomic studies were compared.
The two approaches were found to be complementary to each other and not simply overlapping. Our
findings suggest that comparative gene expression analysis of susceptible and resistant mouse strains
may lead to the identification of factors that could have a role in determining the susceptibility of individuals
to DILD.