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TOXICOLOGY

Coagulation-Dependent Gene Expression and Liver Injury in Rats Given Lipopolysaccharide with Ranitidine but Not with Famotidine

Department of Pharmacology and Toxicology, Center for Integrative Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan (J.P.L., X.D., J.F.M., P.E.G., R.A.R.); Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey (L.D.L.-M., D.M.N., V.M.B., B.D.C., G.H.C.); and Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York (T.P.R.)

In an animal model of drug idiosyncrasy, rats cotreated with nonhepatotoxic doses of lipopolysaccharide (LPS) and ranitidine (RAN) develop hepatocellular injury, whereas rats treated with LPS and famotidine (FAM) do not. The coagulation system and neutrophils (PMNs) are requisite mediators of LPS/RAN-induced liver injury. We tested the hypothesis that unique gene expression in LPS/RAN-treated rats requires coagulation system activation and that these changes are absent in rats given LPS and FAM. Rats were treated with a nonhepatotoxic dose of LPS (44.4 x 10⁶ endotoxin units/kg i.v.) or its vehicle, and then 1 h later, they were treated with heparin (3000 U/kg) or its vehicle. One hour thereafter, they were given RAN (30 mg/kg), FAM (6 mg/kg, a pharmacologically equiefficacious dose, or 28.8 mg/kg, an equimolar dose), or vehicle (i.v.). They were killed 2 or 6 h after drug treatment for evaluation of hepatotoxicity, coagulation system activation, and liver gene expression (2 h only). Statistical filtering of gene array results and real-time polymerase chain reaction identified groups of genes expressed in LPS/RAN-treated rats but not LPS/FAM-treated rats that were either changed or unchanged by heparin administration. For example, LPS/RAN-induced mRNA expression of the inflammatory mediators interleukin-6, cyclooxygenase-2, and macrophage inflammatory protein-2 (MIP-2) was reduced by anticoagulation. Enhancement of serum MIP-2 and plasminogen activator inhibitor-1 concentrations in LPS/RAN-treated rats was prevented by anticoagulation. The results suggest cross-talk between hemostasis-induced gene expression and inflammation (e.g., PMN function) in the genesis of hepatocellular injury in LPS/RAN-treated rats. In contrast, neither the expression of such genes nor hepatocellular necrosis occurred in rats treated with LPS/FAM.

Address correspondence to: Dr. Robert A. Roth, 221 National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824. E-mail: rothr{at}msu.edu