Robert Roth, Ph.D.

Robert Roth, Ph.D.

Pharmacology & Toxicology
Professor
221 Food Safety
1129 Farm Lane
East Lansing, MI 48823
Email: rothr@msu.edu
Phone: 517-353-9841
Fax: 517-432-2310

Fields of Interest: Graduate students and postdoctoral fellows in my laboratory research inflammation as a determinant of susceptibility to the toxic effects of drugs and other chemical agents.

Bob Roth on MSU Scholars

Educational Background

  • 1968 - B.A., Chemistry, Duke University
  • 1975 - Ph.D., Biochemical Toxicology, The Johns Hopkins University
  • 1975-77 - Postdoctoral Fellow, Pulmonary Metabolism & Pharmacology, 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
  • 2003-2017- Director, Graduate Training Program in Environmental and Integrative Toxicological Sciences, Institute for Integrative Toxicology, Michigan State University

Biography & Current Research

Research Synopsis:

Inflammation as a Determinant of Sensitivity to Toxic Agents

Graduate students and postdoctoral fellows in my laboratory research inflammation as a determinant of susceptibility to the toxic effects of drugs and other chemical agents. People frequently experience episodes of inflammation. Our group is interested in how modest inflammation can make individuals particularly sensitive to toxic chemicals. In animal models, we have created 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 modest inflammaton that does not cause liver injury by itself markedly enhances the hepatotoxic effects of aflatoxin B1, as well as other toxic agents that occur in our food or environment. Thus, underlying inflammation 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 interaction of an inflammatory episode with certain drugs underlies some of the rare, idiosyncratic reactions to drugs that people experience. Idiocyncratic, drug-induced liver injury (IDILI) reactions are not well understood, in part because there have been no animal models that have reproduced the liver injury that occurs in people.  By creating a modest inflammatory stress in animals before treating them with a drug, we have developed the first animal models of human IDILI.  In some of the drug-inflammation interaction models that we developed, we have identified factors that contribute to the liver injury.  These include leukocytes such as neutrophils and natural killer cells, the coagulation system, and cytokines such as tumor necrosis factor-alpha and interferon-gamma.  Recent studies in vitro showed that these cytokines interact with drugs that cause idiosyncratic hepatotoxicity to kill hepatocytes.  This cytotoxic interaction involves activation of cell death pathways within hepatoctyes, and it may form the basis for an in vitro assay capable of predicting the potential of drug candidates to cause IDILI in people. 

Current Projects:

  • Development of in vitro assays that predict the ability of drugs to cause idiosyncratic liver injury in people.
  • Understanding mechanisms by which cytokines interact with drugs to injure hepatocytes.

Awards & Achievements

  • Beecham Award for Research Excellence, College of Veterinary Medicine, Michigan State University,1986
  • NIH MERIT Award, 1988
  • Honorary Member, Phi Zeta Honor Society of Veterinary Medicine, 1989
  • Michigan State University Distinguished Professor, 1991
  • Burroughs-Wellcome Toxicology Scholar Award, 1991
  • Kenneth DuBois Award for Achievement in Toxicology, 2001
  • Society of Toxicology/Astra-Zeneca Traveling Lectureship Award, 2006.

Committees & Activities

  • 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
  • Member of Editorial Boards of Journal of Toxicology and Environmental Health, Toxicology and Applied Pharmacology, and General Pharmacology: The Vascular System
  • Member, Technical Committee on the Application of Genomics to Mechanism-based Risk Assessment, Health and Environmental Sciences Institute (HESI), 2004-present
  • Associate Editor, Journal of Pharmacology and Experimental Therapeutics, 2000-present
  • Member, Awards Committee, Society of Toxicology, 2007-2009 (Chair, 2008-09)
  • Member, Hepatotoxcity Working Group, National Center for Toxicological Research, 2009-present.
  • Member, Xenobiotic and Nutrient Disposition and Action Study Section, NIH, 2013-present

Publications

Review Articles

  • Maiuri AR, Breier AB, Turkus JD, Ganey PE, Roth RA. Calcium Contributes to the Cytotoxic Interaction Between Diclofenac and Cytokines. Toxicol Sci. 2016 Feb;149(2):372-84. PubMed Central PMCID: PMC4900219.

  • Miyakawa K, Joshi N, Sullivan BP, Albee R, Brandenberger C, Jaeschke H, McGill MR, Scott MA, Ganey PE, Luyendyk JP, Roth RA. Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice. Blood. 2015 Oct 8;126(15):1835-43. PubMed Central PMCID: PMC4600019.

  • Miyakawa K, Albee R, Letzig LG, Lehner AF, Scott MA, Buchweitz JP, James LP,
    Ganey PE, Roth RA. A Cytochrome P450-Independent Mechanism of Acetaminophen-Induced Injury in Cultured Mouse Hepatocytes. J Pharmacol Exp Ther. 2015 Aug;354(2):230-7. PubMed Central PMCID: PMC4518070.

  • Maiuri AR, Breier AB, Gora LF, Parkins RV, Ganey PE, Roth RA. Cytotoxic Synergy Between Cytokines and NSAIDs Associated With Idiosyncratic Hepatotoxicity Is Driven by Mitogen-Activated Protein Kinases. Toxicol Sci. 2015 Aug;146(2):265-80. PubMed Central PMCID: PMC4607747.

  • Beggs KM, Maiuri AR, Fullerton AM, Poulsen KL, Breier AB, Ganey PE, Roth RA. Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related. Toxicology. 2015 May 4;331:35-46. PubMed Central PMCID: PMC4445241.

  • Poulsen KL, Olivero-Verbel J, Beggs KM, Ganey PE, Roth RA. Trovafloxacin enhances lipopolysaccharide-stimulated production of tumor necrosis factor-α by macrophages: role of the DNA damage response. J Pharmacol Exp Ther. 2014 Jul;350(1):164-70. PubMed Central PMCID: PMC4056269.

  • Poulsen KL, Albee RP, Ganey PE, Roth RA. Trovafloxacin potentiation of lipopolysaccharide-induced tumor necrosis factor release from RAW 264.7 cells requires extracellular signal-regulated kinase and c-Jun N-Terminal Kinase. J Pharmacol Exp Ther. 2014 May;349(2):185-91. PubMed Central PMCID: PMC3989804.

  • Beggs KM, Fullerton AM, Miyakawa K, Ganey PE, Roth RA. Molecular mechanisms of hepatocellular apoptosis induced by trovafloxacin-tumor necrosis factor-alpha interaction. Toxicol Sci. 2014 Jan;137(1):91-101. PubMed Central PMCID: PMC3871929.

For a complete listing of Dr. Roth’s publications