ToxSci Advance Access published online on January 16, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj103
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1 Department of Pharmacology and Toxicology, Center for Integrative Toxicology National Food Safety and Toxicology Center Michigan State University, East Lansing, MI 48824
* To whom correspondence should be addressed. Rats cotreated with lipopolysaccharide (LPS) and ranitidine (RAN) but not LPS and famotidine (FAM) develop hepatocellular injury in an animal model of idiosyncratic drug reactions. Evaluation of liver gene expression in rats given LPS and/or RAN led to confirmation that the hemostatic system, hypoxia and neutrophils (PMNs) are critical mediators in LPS/RAN-induced liver injury. We tested the hypothesis that unique gene expression changes distinguish LPS/RAN-treated rats from rats given LPS or RAN alone and from those cotreated with LPS/FAM. Rats were treated with a nonhepatotoxic dose of LPS (44.4 x 106 endotoxin units/kg, iv) or its vehicle. Two hours thereafter they were given RAN (30 mg/kg, iv), FAM (either 6 mg/kg, a pharmacologically equi-efficacious dose or 28.8 mg/kg, an equimolar dose, iv), or vehicle. They were killed 2 or 6 h after drug treatment for evaluation of hepatotoxicity (2 and 6 h) and liver gene expression (2 h only). At a time before the onset of hepatocellular injury, hierarchical clustering distinguished rats treated with LPS/RAN from those given LPS alone. 205 probesets were expressed differentially to a greater or lesser degree only in LPS/RAN-treated rats compared to LPS/FAM or LPS alone, which did not develop liver injury. These included VEGF, EGLN3, MAPKAPK-2, BNIP3, MIP-2, COX-2, EGR-1, PAI-1, IFN-
Received November 8, 2005
Accepted January 10, 2006
Systems Toxicology
Unique Gene Expression and Hepatocellular Injury in the Lipopolysaccharide-Ranitidine Drug Idiosyncrasy Rat Model: Comparison with Famotidine
James P. Luyendyk 1,
Lois D. Lehman-McKeeman 2,
David M. Nelson 2,
Vasanthi M. Bhaskaran 2,
Timothy P. Reilly 3,
Bruce D. Car 2,
Glenn H. Cantor 2,
Jane F. Maddox 1,
Patricia E. Ganey 1,
and
Robert A. Roth 1 *
2 Discovery Toxicology, Bristol-Myers Squibb, Princeton, NJ, USA
3 Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, NY, USA
Robert A. Roth, E-mail: rothr{at}msu.edu
Abstract 
and IL-6. Expression of these genes was confirmed by real-time PCR. Serum concentrations of MIP-2, PAI-1, IFN- and IL-6 correlated with their respective gene expression patterns. Overall, the expression of several gene products capable of controlling requisite mediators of injury (i.e., hemostasis, hypoxia, PMNs) in this model were enhanced in livers of LPS/RAN-treated rats. Furthermore, enhanced expression of MAPKAPK-2 in RAN-treated rats and its target genes in LPS/RAN-treated rats suggests that p38/MAPKAPK-2 signaling is a regulation point for enhancement of LPS-induced gene expression by RAN.
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