Research Synopsis

Harmful Effects of the Inflammatory Response

Researchers in my laboratory are interested in inflammation as a determinant of susceptibility to the toxic effects of drugs and other chemical agents. All of us experience episodes of inflammation. We are interested in how modest inflammation can make individuals particularly sensitive to toxic chemicals. In rats, we create modest inflammation by administering a small dose of endotoxin (a bacterial product) that by itself is noninjurious. The modest inflammation markedly enhances liver injury caused by drugs and toxic chemicals. For example, aflatoxin B1 is a toxic metabolite produced by a fungus that contaminates nuts and grains. We are exposed to small amounts of it when we eat products made from peanuts or corn, and it is of concern because it can cause liver damage and hepatic cancer in people and animals. We have found that a small dose of endotoxin that is without effect by itself markedly enhances the hepatotoxic effects of aflatoxin B1, as well as other toxic agents that occur in our food or environment. Thus, endotoxin exposure or underlying inflammation from other causes may be an important determinant of sensitivity of people and animals to toxic chemicals.

These findings have led us to a potentially important hypothesis that concurrent inflammation and its interaction with drugs may underlie some of the rare, idiosyncratic reactions people experience when they take certain drugs. In the laboratory, we are working to characterize this inflammation-induced augmentation of toxicity and to explore the cellular and molecular mechanisms that underlie it, with particular emphasis on the role of inflammatory factors such as neutrophils, cytokines and the hemostatic system.

Current Projects

• Role of inflammation in enhancing liver toxicity from drugs and food-borne agents.
• Development novel models to predict drug hepatotoxicity.
• Mechanisms of drug-inflammation interaction—hemostatic system, inflammatory cells and mediators, cell death signaling, etc.
• Characterization of gene expression changes during liver toxicity, using gene array and other technologies.
• Role of hypoxia in liver injury.

Selected Achievements since 2001

Member, Board of Publications, Society of Toxicology, 1998-2002 (Chair, 1999-2001)
Member, Board of Directors, American Board of Toxicology, 1998-2002
Food Safety Specialty Section, Society of Toxicology –President, 2001-2002
Kenneth DuBois Award for Achievement in Toxicology, 2001
Associate Editor, Journal of Pharmacology and Experimental Therapeutics, 2000-present
Member, Technical Committee on the Application of Genomics to Mechanism-based Risk Assessment, ILSI Health and Environmental Sciences Institute (HESI), 2004-present
Member of Editorial Boards of Journal of Toxicology and Environmental Health, Toxicology and Applied Pharmacology, and General Pharmacology: The Vascular System
Society of Toxicology/Astra-Zeneca Traveling Lectureship Award, 2006.

Selected Samples of Publications SInce 2001

Review Articles

Roth, R.A., Luyendyk, J.P., Maddox, J.F. and Ganey, P.E. Inflammation and Drug Idiosyncrasy—Is There a Connection? J. Pharmacol. Exp. Ther., 307:1-8, 2003.

Willett, K.L., Roth, R.A. and Walker, L. Workshop overview: Hepatotoxicity assessment for botanical dietary supplements. Toxicol. Sci. 79: 4-9, 2004.

Ganey, P.E., Luyendyk, J.P., Maddox, J.F. and Roth, R.A. Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. Chemico-Biol. Interact. 150: 35-51, 2004.

Lee, K., Roth, R.A. and LaPres, J.J. Hypoxia, Drug Therapy and Toxicity. Pharmacol. Ther., in press, 2006.

Research Articles

Copple, B.L., Rondelli, C.M., Maddox, J.F., Hoglen, N.S., Ganey, P.E., Roth, R.A. Modes of cell death in rat liver after monocrotaline exposure. Toxicol. Sci. 77: 172-82, 2004.

Maddox, J.F., Domzalski, A.C., Roth, R.A. and Ganey, P.E. 15-DeoxyProstaglandin J2 Enhances Allyl Alcohol-Induced Toxicity in Rat Hepatocytes. Toxicol. Sci. 77: 290-298, 2004.

Kinser, S.K., Sneed, R.A., Roth, R.A. and Ganey, P.E. Neutrophils contribute to endotoxin enhancement of allyl alcohol hepatotoxicity. J. Toxicol. Environ. Hlth. 67: 911-928, 2004.

Harrigan, G.G., LaPlante, R.H., Cosma, G.N., Cockerell, G., Goodacre, R., Maddox, J.F., Luyendyk, J.P. and Roth, R.A. Application of high-throughput Fourier-transform infrared spectroscopy in toxicology studies. Toxicol. Lett. 146: 197-205, 2004.

Luyendyk, J.P., Mattes, W.B., Burgoon, L.D., Zacharewski, T.R., Maddox, J.F., Cosma, G.N., Ganey, P.E. and Roth, R.A. Gene expression analysis points to hemostasis in livers of rats cotreated with lipopolysaccharide and ranitidine. Toxicol. Sci. 80: 203-213, 2004.

Luyendyk, J.P., Maddox, J.F., Green, C.D., Ganey, P.E. and Roth, R.A. Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats. Hepatology 40:1342-51, 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.

Bezdecny SA, Roth RA, Ganey PE. Effects of 2,2',4,4'-tetrachlorobiphenyl on granulocytic HL-60 cell function and expression of cyclooxygenase-2. Toxicol. Sci. 84:328-34, 2005.

Bergheim I, Luyendyk JP, Steele C, Russell GK, Guo L, Roth RA, Arteel GE. Metformin prevents endotoxin-induced liver injury after partial hepatectomy. J Pharmacol Exp Ther., 316:1053-61, 2006.

Maddox, J.F., Luyendyk, J.P., Cosma, G.N., Breau, A.P., Bible, R.H., 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. 212:35-44, 2006.

Waring, J.F., Liguori, M.J., Luyendyk, J.P., Maddox, J.F., Ganey, P.E., Stachlewiz, R.F., North, C., Blomme, E.A.G. and Roth, R.A. Microarray analysis of LPS potentiation of trovafloxacin-induced liver injury in rats indicates a role for proinflammatory chemokines and neutrophils. J. Pharmacol. Exp. Ther. 316:1080-7, 2006.

Crockett, E.T., Galligan, J.J., Uhal, B.D., Harkema, J., Roth, R. and Pandya, K. Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists. BMC Clin Pathol. 6:3 (1-13), 2006.

Luyendyk, J.P., Lehman-McKeeman, Nelson, D.M., Bhaskaran, V.M., Reilly, T.P., Car, B.D., Cantor, G.H., Maddox, J.F., Ganey, P.E. and Roth, R.A. Unique gene expression and hepatocellular injury in the lipopolysaccharide-ranitidine drug idiosyncrasy rat model: comparison with famotidine. Toxicol. Sci. 90: 569-585, 2006.

Luyendyk, J.P., Lehman-McKeeman, L.D., Nelson, D.M., Bhaskaran, V.M., Reilly, T.P., Car, B.D., Cantor, G.H., Deng, X., Maddox, J.F., Ganey, P.E. and Roth, R.A. Coagulation dependent gene expression and liver injury in rats given lipopolysaccharide with ranitidine but not with famotidine. J. Pharmacol. Exp. Ther. 317: 635-43, 2006.

Bergheim, I., Luping, G., Davis, M.A., Lambert, J.C., Beier, J.I., Duveau, I., Luyendyk, J.P., Roth, R.A. and Arteel, G.E. Metformin prevents acute alcohol-induced fat accumulation in the mouse: Critical role of plasminogen activator inhibitor-1. Gastroenterol. 130: 2099-2112, 2006.

Tukov, F.F., Maddox, J.F., Amacher, D.E., Bobrowski, W.F., Roth, R.A. and Ganey, P.E. Modeling Inflammation-Drug Interactions In Vitro: A Kupffer Cell-Hepatocyte Coculture System. Toxicol. In Vitro, 20:1488-99, 2006.

Copple, B.L., Roth, R.A. and Ganey, P.E. Anticoagulation and inhibition of nitric oxide synthase influence hepatic hypoxia after monocrotaline exposure. Toxicol. 225: 128-37, 2006.

Deng, X. , Stachlewitz, R.F., Liguori, M.J., Blomme, E.A.G., Waring, J.F., Luyendyk, J.P., Maddox, J.F., Ganey, P.E. and Roth, R.A. Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and endotoxin translocation. J. Pharmacol. Exp. Ther., in press, 2006.