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 mimics in animals idiosyncratic drug responses. Idiosyncratic responses represent a type of adverse response to drugs that are not apparently dose-related, occur in a very small fraction of people, and for which mechanisms 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 chemicals influence the function of inflammatory cells. Some of these chemicals are common environmental pollutants, such as polychlorinated biphenyls (PCBs) and some pesticides. PCBs activate one type of inflammatory cell, the neutrophil. Neutrophils exposed to PCBs make toxic oxygen species and release contents of their granules; two events that aid in killing bacteria (a good thing) but which also can contribute to tissue injury (a bad thing). A number of signal transduction pathways are activated by PCBs in these cells and are important in the response. In addition, interesting relationships exist between the structures of these chemicals and their biological activities. Furthermore, we have identified changes in expression of a key inflammatory gene in response to PCBs, and we are investigating the mechanisms by which PCBs regulate this gene.

Current Projects:

Ah Receptor-dependent and independent signaling in white blood cells

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

Selected Samples of Publications Since 2001

Barton CC, Barton EX, Ganey PE, Kunkel SL, Roth RA: Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor alpha. Hepatology 33(1): 66-73, 2001.

Ganey PE, Barton YI, Kinser S, Sneed RA, Barton CC, Roth RA: Involvement of cyclooxygenase-2 in the potentiation of allyl alcohol-induced liver injury by bacterial lipopolysaccharide. Toxicol. Appl. Pharmacol. 174(2): 113-121, 2001.

Olivero J, Ganey PE: Participation of Ca(2+)/calmodulin during activation of rat neutrophil by polychlorinated biphenyls. Biochem. Pharmacol. 62(8): 125-1132, 2001.

Moulin F, Copple BL, Ganey PE, Roth RA: Hepatic and extrahepatic factors critical for liver injury during lipopolysaccharide exposure. Amer. J Physiol. 281(6): G1423-G1431, 2001.

Buchweitz JP, Ganey PE, Bursian SJ, Roth RA: Underlying endotoxemia augments toxic responses to chlorpromazine: Is there a relationship to drug discovery? J. Pharmacol. Exp. Ther. 300(2): 460-467, 2002.

Copple BL, Banes A, Ganey PE, Roth RA: Endothelial cell injury and fibrin deposition in rat liver after monocrotaline exposure. Toxicol. Sci. 65(2): 309-318, 2002.

Yee SB, Copple BL, Ganey PE, Roth RA: The temporal relationship between bacterial lipopolysaccharide and monocrotaline exposures influences toxicity: Shift in response from hepatotoxicity to nitric oxide-dependent lethality. J. Toxicol. Environ. Hlth., Part A 65(14): 961-976, 2002.

Luyendyk J, Shores K, Ganey PE, Roth RA: Bacterial lipopolysaccharide exposure alters aflatoxin B1 hepatotoxicity: Benchmark dose analysis for markers of liver injury. Toxicol. Sci. 68(1): 220-225, 2002.

Roth RA, Ganey PE: Biomarkers of organ injury from chemical exposure: Concurrent inflammation as a determinant of susceptibility. In “Environmentally Associated Disease: Technologies, Concepts and Perspectives” (SH Wilson and WA Suk, eds.), Lewis Publ., Boca Raton, FL, Chapter 29, pp. 431-444, 2002.

Copple BL, Woolley B, Banes A, Ganey PE, Roth RA: Anticoagulants prevent monocrotaline-induced hepatic parenchymal cell injury but not endothelial cell injury in the rat. Toxicol. Appl. Pharmacol. 180: 186-196, 2002.

Kinser SH, Copple BL, Roth RA, Ganey PE: Enhancement of allyl alcohol hepatotoxicity by endotoxin requires extrahepatic factors. Toxicol. Sci. 69(2): 470-481, 2002.

Olivero, J., Bezdecny, S.A., and Ganey, P.E.: A molecular motif required for the activation of rat neutrophil phospholipase A2 by organochlorine compounds. Chem. Res. Toxicol. 15: 153-159, 2002.

Yee SB, Ganey PE, Roth RA: The role of Kupffer cells and TNF-alpha in monocrotaline and bacterial lipopolysaccharide-induced liver injury. Toxicol. Sci. 71(1): 124-132, 2003.

Maddox JF, Roth RA, Ganey PE: Allyl alcohol activation of protein kinase Cd leads to cytotoxicity of rat hepatocytes. Chem. Res. Toxicol. 16(5): 609-615, 2003.

Copple BL, Moulin F, Hanumegowda U, Ganey PE, Roth RA: Thrombin and protease-activated receptor-1 agonists promote lipopolysaccharide-induced hepatocellular injury in perfused liver. J. Pharmacol. Exp. Ther. 305(2): 417-425, 2003.

Yee SB, Hanumegowda UM, Hotchkiss JA, Ganey PE, Roth RA: Role of neutrophils in the synergistic liver injury from monocrotaline and bacterial lipopolysaccharide exposure. Toxicol. Sci. 72(1): 43-56, 2003.

Luyendyk JP, Copple BL, Barton CC, Ganey PE, Roth RA: Augmentation of aflatoxin B1 hepatotoxicity by endotoxin: Involvement of endothelium and the coagulation system. Toxicol. Sci. 72(1): 171-181, 2003.

Yee SB, Hanumegowda UM, Copple BL, Shibuya M, Ganey PE, Roth RA: Endothelial cell injury and coagulation system activation during synergistic hepatotoxicity from monocrotaline and bacterial lipopolysaccharide coexposure. Toxicol. Sci. 74(1): 203-214, 2003.

Yee SB, Harkema JR, Ganey PE, Roth RA: The coagulation system contributes to synergistic liver from exposure to monocrotaline and bacterial lipopolysaccharide. Toxicol. Sci. 74(2): 457-469, 2003.

Copple BL, Ganey PE, Roth RA: Liver inflammation during monocrotaline hepatotoxicity. Toxicology 190(3): 155-169, 2003.

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.

Hanumegowda UM, Copple BL, Shibuya M, Malle E, Ganey PE, Roth RA: Basement membrane and matrix metalloproteinases in monocrotaline-induced liver injury. Toxicol. Sci. 76(1): 237-246, 2003.

Copple BL, Rondelli CM, Maddox JF, Hoglen NS, Ganey PE, Roth RA: Modes of cell death in rat liver after monocrotaline exposure. Toxicol. Sci. 77(1): 172-182, 2004.

Harrigan GG, LaPlante RH, Cosma GN, Cockerell G, Goodacre R, Maddox JF, Luyendyk JP, Ganey PE, Roth RA: Application of high-throughput Fourier-transform infrared spectroscopy in toxicology studies: Contribution to a study on the development of an animal model for idiosyncratic toxicity. Toxicol. Lett. 146(3): 197-205, 2004.

Maddox JF, Domzalski AC, Roth RA, Ganey PE: 15-Deoxy prostaglandin J2 enhances allyl alcohol-induced toxicity in rat hepatocytes. Toxicol. Sci. 77(2): 290-298, 2004.

Kinser S, Sneed RA, Roth RA, Ganey PE: Neutrophils contribute to endotoxin enhancement of allyl alcohol hepatotoxicity. J. Toxicol. Environ. Hlth. A 67(12): 911-928, 2004.

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.

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.