Robert A. Roth
Professor, Pharmacology and Toxicology; Graduate Program Director, Environmental and Integrative Toxicological Sciences, Institute for Integrative Toxicology
1129 FARM LN ROOM 221
EAST LANSING MI 48824
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.
Duke University, B.A., 1968, Chemistry
The Johns Hopkins University, Ph.D., 1975, Environ. Toxicology
Yale University School of Medicine, Postdoc, 1975-77, Pulmonary Pharmacology
Selected Professional Activities:
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; Faculty trainer for the NIEHS training grant.
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