The Basic Biology of Aging at the University of Washington
Dave Eaton, Ph.D.

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Email: deaton@u.washington.edu

Dr. Eaton’s laboratory focuses on understanding the biochemical and molecular basis for species and interindividual differences in response to chemical carcinogens. For the past 20 years, Dr. Eaton has been studying the molecular mechanisms that are responsible for large species differences in the carcinogenic activity of the mycotoxin aflatoxin B1 (AFB). Previous studies have shown that mice are highly resistant to the hepatocarcinogenic effects of AFB, whereas rats are highly sensitive. Dr. Eaton’s lab has demonstrated that this remarkable difference is due to the constitutive expression of a single form of the detoxification enzyme glutathione S-transferase A-1-1 (GST) in livers of mice. Dr. Eaton’s laboratory has cloned and sequenced the cDNA for this enzyme, as well as other GST’s in the rat, human, and non-human primate. This particular form of GST in the mouse has 1000-fold higher activity toward AFB-epoxide than a similar form (86% sequence similarity) expressed in rat liver. Human hepatic GST’s demonstrate almost no activity to AFB-epoxide. Site-directed mutagenesis and molecular modeling studies have been completed to more fully understand the mouse enzyme’s unique activity toward the epoxide of AFB.

Other studies in Dr. Eaton’s laboratory have focused on understanding the relative importance of different hepatic cytochrome P450 (CYP) enzymes in the activation and detoxification of AFB. The laboratory has demonstrated that human CYP1A2 has very high catalytic activity toward AFB, and is the primary CYP form responsible for activation of AFB at the low doses encountered in the human diet.

Studies are underway to create a ‘knock out’ mouse in which the gene for the specific GST with high activity toward AFB-epoxide is removed. We are examining whether common “phytochemicals” (plant-derived, biologically active substances) found in the diet can alter the way biotransformation enzymes are expressed in human liver cells, with special emphasis on how dietary factors can influence how aflatoxin is activated and detoxified in the body.

Another area of study in Dr. Eaton’s laboratory is whether genetic differences in the formation and elimination of reactive forms of estrogen, known as “catechol estrogens,” might influence a woman’s risk of developing endometrial cancer. Catechol estrogens are produced from circulating estrogen by specific forms of cytochrome P450, and can be further metabolized to quinones, which may “redox cycle” to produce reactive oxygen that can damage DNA. There are other enzymes that can eliminate these catechol estrogens. In this study, funded by the National Institute of Aging, we aim to understand whether genes for these enzymes are expressed in human endometrial tissue, and whether genetic differences can influence the extent of oxidative damage to DNA that occurs over time.

Dr. Eaton is the Associate Dean for Research in the School of Public Health and Community Medicine at the University of Washington. His academic appointment is in the Department of Environmental Health, and he currently serves as Director of the UW/NIEHS Center for Ecogenetics and Environmental Health. He is also Deputy Director for a large, multi-investigator consortium/Center grant from the NIEHS in the area of Toxicogenomics. Dr. Eaton has two active NIH RO1 grants: one supports his aflatoxin research, and the other focuses on estrogen metabolism and endometrial cancer risk. He also directs an NIEHS-funded K-12 Curriculum Development program to incorporate principles of environmental health sciences into K-12 curricula.

Selected Relevant Publications
Kelly JD, Eaton DL, Guengerich FP, Coulombe RA Jr. Aflatoxin B1 activation in human lung. Toxicol Appl Pharmacol 144:88-95, 1997.

Neal GE, Eaton DL, Judah DJ, Verma A. Metabolism and toxicity of aflatoxins M1 and B1 in human- derived in vitro systems. Toxicol Appl Pharmacol 151:152-158, 1998.

Eaton DL. Biotransformation enzyme polymorphisms and pesticide susceptibility. NeuroTox 21: 101-111, 2000.

Bammler TK, Slone DH, Eaton DL. Effects of chemointervention on aflatoxin B1 biotransformation in non-human primates. Toxicol Sci 54:30-41, 2000.

Wang CH, Bammler TK, Ou YY, Kelly EJ, Eaton DL. Mu-class GSTs are responsible for aflatoxin B1-8, 9-epoxide conjugating activity in the non-human primate Macaca fascicularis liver. Toxicol Sci 56:26-36, 2000.

Johnson DB, Eaton DL, Wahl PW, Gleason C. Public health nutrition practice in the United States. J Am Diet Assoc 101:529-534, 2001.

Eaton DL, Klaassen CD. Principles of toxicology. In: Casarett & Doull’s Toxicology: The Basic Science of Poisons, 6th edition. CD Klaassen, ed. pp 11-34. McGraw-Hill, New York, 2001.

Kelly EJ, Erickson KE, Sengstag C, Eaton DL. Expression of human microsomal epoxide hydrolase in Saccharomyces cerevisiae reveals a functional role in aflatoxin B1 detoxification. Toxicol Sci 65:35-42, 2002.

Eaton DL, Robertson WO. Toxicology. In: Textbook of Occupational and Environmental Medicine, 2nd ed. L Rosenstock, M Cullen, eds. WB Saunders Company, New York, in press.