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.
Welch
Kevin D
KD
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA. WelchKD@nhlbi.nih.gov
Reilly
Timothy P
TP
Bourdi
Mohammed
M
Hays
Thomas
T
Pise-Masison
Cynthia A
CA
Radonovich
Michael F
MF
Brady
John N
JN
Dix
David J
DJ
Pohl
Lance R
LR
D000082:Acetaminophen / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018840:HSP70 Heat-Shock Proteins / Q000172:deficiency; D007274:Injections, Intraperitoneal; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053495:Osteopontin; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012307:Risk Factors; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D013997:Time Factors
D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000082:Acetaminophen