Robert A. Roth, Distinguished Professor
1968, B.A., Duke University
1975, Ph. D., The Johns Hopkins University
1975-77, Postdoctoral Fellow, Yale University
1977-82 Assistant Professor, Pharmacology & Toxicology, Michigan State University
1982-87 Associate Professor, Pharmacology & Toxicology, Michigan State University
1987-present, Professor, Pharmacology & Toxicology, Michigan State University
2003-present, Director, Graduate Training Program in Environmental and Integrative Toxicological Sciences, Center for Integrative Toxicology
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 that results 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.
- 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.
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. 113: 229-246, 2007.
Research Articles
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., 319: 1191-99, 2006.
Bezdecny, S.A., Karmaus, P., Roth, R.A. and Ganey, P.E. 2,2´,4,4´-Tetrachlorobiphenyl upregulates cyclooxygenase-2 in HL-60 cells via p38 mitogen-activated protein kinase and NF-κB. Toxicol. Appl. Pharmacol. 221: 285-294, 2007.
Ganey, P.E., Luyendyk, J.P., Newport, S.W., Eagle, T. M., Maddox, J.F., Mackman, N. and Roth, R.A. Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice. Hepatol. 46: 1177-86, 2007.
Tukov, F.F., Luyendyk, J.P., Ganey, P.E. and Roth, R.A. Role of tumor necrosis factor-alpha in lipopolysaccharide/ranitidine-induced inflammatory liver injury. Toxicol. Sci. 100: 27-80, 2007.
Deng, X., Luyendyk, J.P., Zou, W., Lu, J., Malle, E., Ganey, P.E. and Roth, R.A. Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine. J. Pharmacol. Exp. Ther. 322: 852-861, 2007.
Shaw. P.J., Hopfensperger, M.J., Ganey, P.E. and Roth, R.A. Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol. Sci. 100: 259-66, 2007.
Deng, X., Lu, J., Lehman-McKeeman, L.D., Malle, E., Crandall, D., Ganey, P.E. and Roth, R.A. p38 MAPK-dependent TNF-{alpha} converting enzyme is important for liver injury in hepatotoxic interaction between lipopolysaccharide and ranitidine. J Pharmacol Exp Ther., in press, 2008.