Contact Info:Email: ganey@msu.edu Phone: (517) 432-1761 Fax: (517) 353-8915

Research Synopsis:

Inflammation/chemical interaction and toxicity
The primary focus of our research is to understand the mechanisms and consequences of interactions between the inflammatory response and chemicals that lead to toxicity. The chemicals of interest range from environmental chemicals to drugs, and the target of interest is the liver.

One project involves inflammation/drug interaction that leads to liver injury in experimental animals. These responses mimic idiosyncratic, adverse drug responses that occur in people. Idiosyncratic responses occur in a very small fraction of people, and dose-response relationships are not obvious. The mechanisms underlying these reactions are unknown. Liver is a frequent target, and some of the more serious idiosyncratic reactions in liver can lead to the necessity of liver transplantation or even death.

A problem with understanding these reactions is the lack of animal models that mimic the response. We have found that for many drugs this type of adverse reaction can be reproduced in experimental animals by cotreatment with drug and an agent to induce inflammation. We are using these animal models to explore mechanisms of hepatotoxicity and drug/inflammation interaction.

In addition, we are investigating the possibility that differential changes in gene expression in livers of these animals may allow us to predict the potential for new drugs and drugs under development to cause this type of adverse response. If the propensity to cause idiosyncratic liver injury can be identified early in drug development, much human suffering can be prevented.

Another project focuses on molecular mechanisms by which certain types of environmental chemicals influence the inflammatory response. The chemicals of interest in these studies are ones that bind to a receptor known as the aryl hydrocarbon or Ah receptor. Dioxin (also called TCDD) is the most well known chemical in this class. We have demonstrated that mice treated with TCDD have a more robust inflammatory response when they are exposed to a bacterial product known as lipopolysaccharide.  We are investigating signal transduction pathways activated by lipopolysaccharide and by TCDD to try to understand the molecular mechanisms of this interaction.

Current Projects:
== Influence of Ah Receptor Ligands on Inflammatory Responses: Consequences for Tissue Injury and Gene
== Expression
== Gene Expression in drug-inflammation models as predictive of idiosyncratic adverse drug reactions.

Selected Achievements since 2001:

Honors/Awards
Past President, Michigan Regional Chapter of the Society of Toxicology, 2000-2001
Pfizer Excellence in Research Award, 2002.

ASPET
Secretary-Treasurer, Toxicology Division, 2002-2004.

Society of Toxicology
Member, Continuing Education Committee, 1998-2001
Member, Membership Committee, 2001-2004; Chair, 2003-2004
Member, Awards Committee, 2005-2007
Chair, Society of Toxicology Member Services Strategy Committee, 2006-2007
Councilor, Society of Toxicology, 2008-2010

Selected Samples of Publications Since 2003
Deng X, Liguori MJ, Sparkenbaugh EM, Waring JF, Blomme EA, Ganey PE, Roth RA. Gene expression profiles in livers from iclofenac-treated rats reveal intestinal bacteria-dependent and -independent pathways associated with liver injury. J Pharmacol Exp Ther. Sep 18. [Epub ahead of print] 2008.

Deng X, Lu J, Lehman-McKeeman LD, Malle E, Crandall DL,Ganey, PE, Roth RA. p38 mitogen-activated protein kinase-dependent tumor necrosis factor-alpha-converting enzyme is important for liver injury in hepatotoxic interaction between lipopolysaccharide and ranitidine. J Pharmacol Exp Ther. 326(1), 144-152, 2008.

Ganey PE, Luyendyk JP, Newport SW, Eagle TM, Maddox JF, Mackman N, Roth RA. Role of the coagulation system in 
acetaminophen-induced hepatotoxicity in mice. Hepatology 46(4), 1177-1186, 2007.

Tukov FF, Luyendyk JP, Ganey PE, Roth RA. The Role of Tumor Necrosis Factor alpha in 
Lipopolysaccharide/Ranitidine-induced Inflammatory Liver Injury. Toxicol Sci 100(1), 267-280, 2007.

Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA. Lipopolysaccharide and trovafloxacin coexposure in mice causes 
idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci. 100(1), 259-266, 2007.

Bezdecny SA, Karmaus P, Roth RA, Ganey PE. 2,2',4,4'-Tetrachlorobiphenyl upregulates cyclooxygenase-2 
in HL-60 cells via p38 mitogen-activated protein kinase and NF-kappaB. Toxicol Appl Pharmacol 221(3), 
285-294, 2007. 

Deng X, Luyendyk JP, Zou W, Lu J, Malle E, Ganey PE, Roth RA. Neutrophil interaction with the hemostatic 
system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine. J Pharmacol Exp 
Ther 322(2), 852-861, 2007. 

Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I, Klaunig JE. Role of the Kupffer Cell in Mediating Hepatic 
Toxicity and Carcinogenesis. Toxicol Sci 96, 2-15, 2007. 

Deng X, Stachlewitz RF, Liguori MJ, Blomme EA, Waring JF, Luyendyk JP, Maddox JF, Ganey PE, Roth RA. 
Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacterial translocation. 
J Pharmacol Exp Ther 319(3), 1191-1199, 2006.

Copple BL, Roth RA, Ganey PE. Anticoagulation and inhibition of nitric oxide synthase influence hepatic hypoxia 
after monocrotaline exposure. Toxicology 225(2-3), 128-137, 2006.

Tukov FF, Maddox JF, Amacher DE, Bobrowski WF, Roth RA, Ganey PE. Modeling inflammation-drug interactions 
in vitro: a rat Kupffer cell-hepatocyte coculture system. Toxicol In Vitro 20(8), 1488-99, 2006. 

Luyendyk JP, Lehman-McKeeman LD, Nelson DM, Bhaskaran VM, Reilly TP, Car BD, Cantor GH, Maddox JF, 
Ganey PE, Roth RA. Unique gene  expression and hepatocellular injury in the lipopolysaccharide-ranitidine drug
 idiosyncrasy rat model: Comparison with famotidine. Toxicol Sci 90(2), 569-585, 2006.


Waring  JF, Liguori MJ, Luyendyk JP, Maddox JF, Ganey PE, Stachlewitz RF, North C, Blomme EA, Roth RA. 
Microarray analysis  of LPS potentiation of trovafloxacin-induced liver injury in rats suggests a  role for 
proinflammatory chemokines and neutrophils. J Pharmacol Exp Ther 316,  1080-1087, 2006.



Luyendyk JP, Lehman-McKeeman LD, Nelson DM, Bhaskaran VM, Reilly TP, Car BD, Cantor GH, Deng X, 
Maddox JF,  Ganey PE, Roth RA. Coagulation-dependent  gene expression and liver injury in rats given 
lipopolysaccharide with ranitidine but not with famotidine. J Pharmacol Exp Ther 317, 635-643, 2006. 

 
Maddox  JF, Luyendyk JP, Cosma GN, Breau AP, Bible RH Jr, Harrigan GG, Goodacre R,  Ganey PE, Cantor GH, 
Cockerell GL, Roth RA. Metabonomic evaluation of  idiosyncrasy-like liver injury in rats cotreated with ranitidine and  
lipopolysaccharide. Toxicol Appl Pharmacol 212, 35-44, 2006.


Luyendyk, J.P., Shaw, P.J., Green, C.D., Maddox, J.F.,  Ganey, P.E. and Roth, R.A. Coagulation-mediated hypoxia and  
neutrophil-dependent hepatic injury in rats given lipopolysaccharide and  ranitidine. J. Pharmacol. Exp. Ther. 
414: 1023-1031, 2005.



Maddox, J.F., Luyendyk, J.P., Cosma, G.N., Breau, A.P., Bible, R.H., Jr.,  Harrigan, G.G., Goodacre, R., 
Ganey, P.E., Cantor, G.H., Cockerell, G.L., and  Roth, R.A.: Metabonomic evaluation of idiosyncrasy-like liver 
injury in rats  cotreated with ranitidine and lipopolysaccharide. Toxicol. Appl. Pharmacol.,  2005.

          
Bezdecny,   S.A., Roth,  R.A., and Ganey, P.E.: Effects of 2,2=,4,4=-tetrachlorobiphenyl on granuloxytic  HL-60 cell 
function and expression of cyclooxygenase-2. Toxicol. Sci. 84:  328-334, 2005.



Luyendyk JP, Mattes WB, Burgoon LD, Zacharewski TR,  Maddox JF, Cosma GN, Ganey PE Roth RA: Gene 
expression analysis points to  hemostasis in livers of rats cotreated with lipopolysaccharide and ranitidine. 
Toxicol. Sci. 80(1): 203-213, 2004.

          
Ganey   PE, Luyendyk JP, Maddox JF, Roth  RA: Adverse hepatic drug reactions: Inflammatory episodes as 
consequences and  contributor. Chem. Biol. Interact. 150(1): 3551, 2004.



Luyendyk JP, Maddox JF, Green CD, Ganey PE, Roth RA:  Role of hepatic fibrin in idiosyncrasy-like liver injury from  
lipopolysaccharide-ranitidine coexposure in rats. Hepatology 40(6): 1342-1351,  2004.


Roth RA, Luyendyk JP, Maddox JF, Ganey PE:  Inflammation and drug idiosyncrasy—Is there a connection? 
J. Pharmacol. Exp. Ther. 307(1): 1-8, 2003.




Luyendyk JP, Maddox JF, Cosma GN, Ganey PE,  Cockerell GL, Roth RA: Ranitidine treatment during a 
modest inflammatory  response precipitates idiosyncrasy-like liver injury in rats. J. Pharmacol.  
Exp. Ther. 307(1): 9-16, 2003.