This year we have continued our studies of the molecular basis of drug-induced hepatitis (DIH), a rare but often life-threatening toxicity that is a major reason for clinical trials of drugs being stopped and drugs being withdrawn from clinical use post-marketing. Although we have discovered in mouse studies that the disruption of key regulatory factors (COX-2, IL-6, IL-10) dramatically increased susceptibility, no single factor seems to be absolute. In order to better understand this polygenicity, we now report a genomic approach aimed at uncovering combinations of ?inherent? differences that might more aptly mimic situations seen in patients. Susceptibility differences to the well-known analgesic/antipyretic drug, acetaminophen (APAP), were investigated using 8 common strains of mice. The rank order of liver damage following APAP treatment was C57Bl/6>C3H/HeOu>> 129S6/SvEv=BALB/c>C3H/He>ICR=DBA/2>>>SJL. Lethality mimicked these rankings with noteworthy differences that included delayed lethality of C57Bl/6, ~40% deaths of ICR, and a lack of any deaths in DBA and SJL mice. Metabolic analyses of these 4 strains showed no differences in total APAP-protein adducts or CYP2E1 levels, but did reveal significantly lower levels of specific adducts in SJL mice. Using a microarray platform to monitor 36K genes, hepatic gene expression time profiles were obtained for C57Bl/6, DBA, ICR and SJL strains in the absence and presence of APAP toxicity. The expression of >2000 ESTs and known genes, including many inflammatory and stress responsive regulators, showed unique positive and negative correlations with toxicity suggesting possible mechanistic functions. A confirmed increase of heat shock proteins 40 and 70 in resistant SJL mice represents one example. Further delineation of the factors that correlate with differential toxicity profiles and analysis of ongoing F1 cross studies should facilitate our understanding of DILD and begin to uncover candidates whose altered expression might predict susceptibility.
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