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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 9, 2006; DOI: 10.1124/jpet.105.096305

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Received for publication September 27, 2005.
Revised January 4, 2006.
Accepted for publication January 5, 2006.

Coagulation dependent gene expression and liver injury in rats given lipopolysaccharide with ranitidine but not with famotidine

James P Luyendyk 1, Lois D. Lehman-McKeeman 2, David M Nelson 2, Vasanthi M Bhaskaran 3, Timothy P. Reilly 3, Bruce D Car 3, Glenn H Cantor 3, Xiaomin Deng 1, Jane F. Maddox 1, Patricia E Ganey 1, Robert A. Roth 1*

1 Michigan State University 2 Bristol Myers Squibb 3 Bristol-Myers Squibb

* Address correspondence to: E-mail: rothr{at}msu.edu

Abstract

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, iv) or its vehicle, then one hour later with heparin (3000 U/kg) or its vehicle. One hour thereafter they were given RAN (30 mg/kg), FAM (6 mg/kg: a pharmacologically equi-efficacious dose, or 28.8 mg/kg: an equimolar dose), or vehicle (iv). 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 PCR 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 IL-6, COX-2, and MIP-2 was reduced by anticoagulation. Enhancement of serum MIP-2 and PAI-1 concentrations in LPS/RAN-treated rats was prevented by anticoagulation. The results suggest crosstalk 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.


Key words: Gene array, Inflammation, coagulation system, drug idiosyncrasy, hepatotoxicity, lipopolysaccharide




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