Dr. David L. Eaton

My laboratory is focused in the area of chemical carcinogenesis. Primary interests focus on the role of specific xenobiotic biotransformation enzymes as determinants of species and individual susceptibility to environmental carcinogens. In particular, mylab has been studying the natural mycotoxin, aflatoxin B1 (AFB), which is a potent carcinogen in rats (but not mice), and is a common contaminate of peanuts, corn and occasionally other nuts and grains.

As a toxicologist, I am interested in the way that chemicals, both natural and human-made, can cause or modify toxic responses in the body. Once a chemical enters the body via the lung, the skin or the gastrointestinal tract, it is usually metabolized (biotransformed) in the liver or other tissues in an effort to remove the chemical from the body. I'm interested in the enzymes in the body that biotransforms chemicals, and how this process of biotransformation can determine whether a particular chemical might contribute to the risk of developing cancer but the processes I study are also relevant to chemical causes of birth defects, chronic neurological diseases such as Parkinson's or Alzheimer's disease, and other forms of toxicity. Recently, my laboratory has begun investigating the molecular mechanisms by which common plant chemicals (phytochemicals) seem to protect against the development of some types of cancer. Specifically, we are interested in how phytochemicals in broccoli and other cruciferous vegetables change the way the liver metabolizes drugs and non-drug chemicals.

Specific grants that support my research program are described below:

Program/Grant Name: Center for Ecogenetics and Environmental Health

Funding Agency: NIH/NIEHS (P30 ES07033)
Description:
Many diseases of public health importance, such as most cancers, Alzheimer's Disease, Parkinson's disease, asthma, andeven birth defects, arise through a complex interaction of genetics and environment. Investigators in the Center for Ecogenetics and Environmental Health are conducting research to understand how specific genetic traits increase or decrease an individual's likelihood of contracting a chronic disease or illness. For example, researchers are studying how genetic differences in the way people break down (metabolize) drugs and other chemicals might increase their chances of getting cancer when exposed to potentially cancer-causing chemicals in their workplace, diet or lifestyle activities (e.g., smoking). Other researchers in the Center are studying genetic traits that, when combined with exposure to substances in the diet or general environment, make individuals more likely to develop chronic neurological diseases such as Parkinson's disease. Other researchers are investigating the link between genetics and asthma, and environmental factors that might cause birth defects in genetically susceptible individuals. In addition to basic research, the Center includes a core devoted to the study of ethical, legal and social issues related to the use, and potential misuse, of genetic susceptibility information. The Community Outreach and Education Program within the CEEH develops workshops and educational materials, and promotes community education, in the environmental health sciences. Although based in the School of Public Health and Community Medicine, CEEH Investigators come from a variety of schools and departments across the University. Research findings from CEEH investigators will help unravel how genetics and environment interact to produce disease, and are an important extension of the exciting new information coming from the Human Genome Project.

Web URL: http://depts.washington.edu/ceeh/

Program/Grant Name: Species Differences in Aflatoxin Carcinogenesis
Funding Agency: NIH/NIEHS (R01 ES-05780)
Description:
Aflatoxin B1 (AFB) is a fungal toxin produced by a common mold that grows on corn, peanuts and other human foodstuffs. Laboratory studies in rats have demonstrated that AFB is among the most potent cancer-causing chemicals ever discovered, causing almost exclusively cancer of the liver. However, mice seem completely resistant to the cancer causing effects of AFB. Although AFB in foodstuffs in the United States and other developed countries is tightly regulated and liver cancer incidence is relatively low, in some parts of the world liver cancer occurs at alarming rates, and a combination of AFB in the diet and hepatitis virus infection seem responsible. This research program studies how AFB is activated and detoxified by human liver, and how natural and synthetic chemicals in the diet can modify the cancer-causing potency of AFB.These studies, conducted in collaboration with investigators at the University of Pittsburgh, utilize freshly isolated human liver cells in culture to study how certain plant-derived chemicals commonly found in the diet can help detoxify AFB. Through such studies it is hoped that dietary recommendations or perhaps even supplements could be designed that would greatly decrease the incidence of liver cancer in regions of the world where aflatoxins are commonly found in the diet. The results will also be useful in understanding how chemicals can cause cancer, and how genetic difference between humans might result in increased or decreased cancer risk following exposure to cancer-causing chemicals such as AFB.

rogram/Grant Name: Isothiocyanates as a specific antagonist to the Pregane X-Receptor.
Funding Agency: NIH R01 GM079280-01A1
Description:
This grant supports a phase I clinical trial that is based on our previous observations that the isothiocyanaate, sulforaphane (SFN) down-regulates transcription of the gene for the drug metabolizing enzyme CYP3A4 . Our previous work revealed that SFN acts as an effective antagonist of ligand binding to the Pregnane X-Receptor (PXR; also called the Steroid and Xenobiotic Receptor, SXR). This work was published in 2007 (Zhou et al., Mol Pharmacol 71:220-229, 2007). Several drugs and environmental chemicals can act as exogenous ligands to PXR, and exposure then results in the `up-regulation of CYP3A4 expression and activity. This is among the most common causes of adverse drug-drug interactions. Eaton and colleagues demonstrated that SFN was highly effective in preventing CYP3A4 induction via the widely used anti-TB drug, Rifampin. Based on this observation, a new NIH grant was funded in October of 2007 to conduct a phase I clinical trial to determine if SFN can block CYP3A4 induction by rifampin in vivo (R01GM079280-A1). This has substantial public health implications, because Rifampin is an important first line drug in the treatment of TB. However, because Rifampin greatly induces CYP3A4 (by activating the PXR receptor in the liver) during the treatment regimen for TB, it cannot be used in HIV/AIDS patients undergoing antiretroviral therapy because the antiretroviral drugs are quickly metabolized to ineffective products via the induced CYP3A4. If the clinical trial demonstrates that SFN can block Rifampin-mediated induction of CYP3A4, it could provide an important new tool to treat TB in HIV/AIDS patients. TB is the most common opportunistic infection in HIV/AIDS patients world wide.

KEY PROFESSIONAL ACTIVITIES (Since 1995):
Fellow, Academy of Toxicological Sciences (FATS) 2000;
President, Society of Toxicology 2001-2002;
VicePresident (and VP-elect), Society of Toxicology, 1999-01;
Member, External Science Advisory Board, NIEHS Center for Environmental Health Sciences, University of California-Davis, 1999-;
Editorial Board, Chemico-Biological Interactions, 1998-;
Member, Environmental Genome Working Group, NIEHS, 1997-98;
Councilor, Mechanisms Specialty Section, Society of Toxicology, 1997-99;
Member, Board of Environmental Studies and Toxicology, National Academy of Sciences/National Research Council, 1996-99;
Member, External Science Advisory Board, Center for Research on Environmental Disease, Univeristy of Texas-MD Anderson Cancer Center, Smithville, TX, 1996-;
Secretary, Society of Toxicology, 1996-98;
Visiting Scientist, International Agency for Research on Cancer (IARC), Lyon, France, 9/1/95-12/1/96;
President, Mechanisms Specialty Section, Society of Toxicology, 1996-97;
Associate Editor, Toxicology and Applied Pharmacology, 1996-99;
Editorial Board, Oncology Reports, 1994-97;
Editorial Review Board, Environmental Health Perspectives, 1993-97.

Occasionally serve as a consultant / expertise witness on issues relating to ''toxic torts'' or other legal or policy aspects of toxic substances. Specific areas of expertise include acute poisonings and/ or chronic health risks from: pesticides, metals (esp. arsenic), hydrogen sulfide, cyanide, carbon monoxide, dioxins, PCBs.