Table of contents  •  Who we are ... people and programs  •  Where we've been ... and where we're going  •  
Facts and figures  •  Acknowledgments


What we do ... and whom we serve  •  Probing genetic variations

Sacred objects,
safely returned

Beyond the laboratory walls

Breathing safely in the dusty trades

Particulate air pollution

Probing genetic variations

Suppose your doctor wanted to try a promising new medicine, but wasn't sure how you would respond. Suppose your job involved exposure to a chemical that causes reactions in only a small percentage of people, and you wanted to know if you would be one of them.

Your genetic makeup may determine how well you respond to a new medicine or whether a chemical exposure will make you sick. Professor Curt Omiecinski and his laboratory colleagues are studying the interrelationships of toxicology with genetics.

Genes and the environment

The human genome consists of about 3 billion bases, or building blocks of DNA, Omiecinski said.

Curt Omiecinski, director of the Department'/s Toxicology program

Although people share a high degree of genetic similarity, everyone's genetic code is different. Genetic variation at the level of single base changes between common genes is termed a single nucleotide polymorphism, or SNP (pronounced "snip"). SNPs and other types of genetic alterations likely contribute to differences in the way individuals respond to chemical exposures or their risk of suffering from adverse drug reactions. To predict an individual's chemical response profile, researchers need to understand how the body processes the chemical and how the "genetic fingerprint" of the individual affects these processes.

The laboratory has characterized polymorphisms (different forms) based on single nucleotide changes in several different enzymes that help the body break down and eliminate poisons. For example, they have discovered SNPs in an enzyme system termed epoxide hydrolase-actually a family of enzymes that metabolize certain cancer-causing chemicals. The laboratory has also worked with researchers in the UW medical genetics program and discovered SNPs in an enzyme named paraoxonase, which is responsible for metabolizing certain pesticides and neurotoxins.

Omiecinski is director of the Department's Toxicology program and also directs the biomarker laboratory, which is an arm of the DEH Center for Ecogenetics and Environmental Health. Epidemiological studies are being conducted to determine potential associations of these genetic variants with diseases such as lung cancer and Parkinson's.

Together with collaborators from other parts of DEH, Epidemiology, and the Fred Hutchinson Cancer Research Center, the Department's molecular biomarker laboratory is working to examine individual differences in genetics and how they affect relative risks of environmentally associated diseases.

Microarrays

Professor Omiecinski is using DNA microarrays or "chips," to provide instant information about how someone's genes respond to a particular drug or poison. This new technique is a powerful method that enables the lab to study the phenomenon of genetic variation as it relates to an individual's ability to detoxify chemical substances. A cell exposed to a poison may start producing large quantities of enzymes used to break down toxic substances or to repair DNA. Our genes control enzyme production. By tracking certain enzymes it is possible to determine how a cell's genes react to a particular exposure. Previously, investigators could examine changes in the enzyme production, or expression, of just one or a few genes at a time, Omiecinski said. The new microarray technique can show the expression of thousands of genes simultaneously-potentially the entire human genome-in response to an exposure.

The chip testing procedure involves the use of small glass slides that contain robotically applied arrays of up to 50,000 densely packed spots of DNA. Each spot represents sequences from a different gene. The microarrays can be "probed" with various RNA samples collected from cells or tissues that have been subjected to chemical or drug treatment. The RNA samples are labeled with colored fluorescent dyes and incubated with the DNA arrays to determine which genes are expressed (turned on) and how they respond to a particular exposure. A gene that is active will glow on the slide. The more active it is, the brighter it will glow. The biological picture is captured as binary data that computers can analyze. The Omiecinski laboratory has been using microarray experiments to study environmental chemicals that act as gene inducers, increasing gene expression in liver cells. The liver is the body's primary organ for detoxifying or metabolizing chemical substances. Understanding the impact of gene inducers could help researchers and physicians pre-dict how someone will respond to a drug or chemical.

Postdoctoral Fellow Tao Wang uses a fluorescence microscope to study enzyme activity in mouse liver cells

The future In addition to the cultured cell approaches, the DNA microarray technology may eventually replace animal tests, which are now used to evaluate the safety or toxicity of chemicals and drugs.

The overall scientific area encompassed by these genomic approaches as they apply to toxicology is termed "toxicogenomics." Together with the other investigators in the DEH Toxicology program, Omiecinski is engaged in a variety of toxicogenomic strategies to advance basic science with the ultimate goal of better predicting risks and outcomes of chemical exposures.

For further reading

Beck NB, Sidhu JS, Omiecinski CJ. Baculovirus vectors repress phenobarbital-mediated gene induction and stimulate cytokine expression in primary cultures of rat hepatocytes. Gene Therapy. 7:1274-83, 2000.

Fretland AJ, Omiecinski CJ. Epoxide hydrolases: biochemistry and molecular biology. Chem-Biol Interac 129:41-59, 2000.

Molecular biomarker laboratory Web site:
http://depts.washington.edu/ceeh/ServiceCores/SC2/SC2.html

National Human Genome Research Institute: Microarray Project Web site. http://www.nhgri.nih.gov/dir/Microarray/main.html

Omiecinski CJ. Epoxide Hydrolase. In: Metabolic Drug Interactions, Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M, eds. Lippincott Williams & Wilkins, Philadelphia, PA: pp. 205-216, 2000.

Omiecinski CJ, Remmel RP, Hosagrahara VP. Concise review of the cytochrome P450s and their roles in toxicology. Tox Sci 48:151-156, 1999.

Omiecinski laboratory Web site:
http://faculty.washington.edu/cjo/

Sandberg M, Hassett C, Adman ET, Meijer J, Omiecinski CJ. Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms. J Biol Chem 275:28873-81, 2000.

Schilter B, Andersen MR, Acharya C, Omiecinski CJ. Activation of cytochrome P450 gene expression in the rat brain by phenobarbital-like inducers. J Pharmacol Exp Ther 294:916-22, 2000.

Sidhu JS, Liu F, Boyle SM, Omiecinski CJ. PI3K inhibitors reverse the suppressive actions of insulin on CYP2E1 expression by activating stress-response pathways in primary rat hepatocytes. Mol Pharmacol 59:1138-46, 2001.