TRAINING IN PHARMACOLOGY, TOXICOLOGY & PHARMACEUTICAL SCIENCES 2008 ASPET SUMMER UNDERGRADUATE RESEARCH FELLOWSHIP OPPORTUNITY at the UNIVERSITY OF CINCINNATI
The Division of Molecular Toxicology & Environmental Genetics, College of Medicine is pleased to offer this research project as part of the 2008 ASPET SURF Training Program offered by the Department of Pharmacology & Cell Biophysics.  Students interested in this project are advised to contact Professor Nebert to discover more about the project, learn what your responsibilities will be during the ten-week research training program.
2008 ASPET Project #:  08 - 007 Faculty Supervisor/Mentor: Daniel W. Nebert, M.D. Professor Environmental Genetics & Molecular Toxicology (EGMT) College of Medicine, University of Cincinnati Email:  dan.nebert@uc.edu
Project Title: Genetic Basis of Molecular Mechanisms of Toxicity and Cancer by Drugs and Environmental Chemicals
Research Program:  The overriding theme of the Nebert laboratory has been to understand why two different people, receiving the same dose of drug or other environmental chemical, respond differently––due to their underlying genetic predisposition. Environmental chemicals include cigarette smoke, polycyclic aromatic hydrocarbons, dioxin, heavy metals, and occupationally hazardous substances. The response differences can include efficacy, therapeutic failure, or adverse reactions (toxicity or cancer). Toxicity can include oxidative stress. Fields of interest for investigating this theme have been mouse genetics, human genetics, pharmacogenetics, pharmacogenomics, environmental toxicology, molecular biology and biochemistry, receptorology, phenotype-genotype association studies, clinical genomics, evolutionary biology, and comparative genomics. Within this research program we are: (1) exploring the role of the aromatic hydrocarbon receptor in toxicity and cancer; (2) searching for a gene that confers resistance to heavy metal-induced toxicity; and (3) using oral benzo[a]pyrene (BaP; a chemical that is present in cigarette smoke and other combustion processes) in various knockout mouse lines to show relationships between the entrance of undesirable chemicals into the body and toxicity or cancer in a target organ, as a function of the presence or absence of specific enzymes. Role of the Aromatic Hydrocarbon Receptor in Toxicity and Cancer: The Nebert laboratory discovered in the 1970s that there were genetic differences among inbred mouse strains, in that some mice show an increased risk of toxicity and cancer when treated with dioxin or benzo[a]pyrene while other mice do not—even though they are exposed to the same dose of these environmental chemicals. The mice exhibiting increased risk have a “high-affinity” aromatic hydrocarbon receptor (AHR), and those displaying lower risk have a “poor-affinity” AHR, meaning that—at whatever dose of BaP or dioxin—more of these environmental chemicals bind to the AHR in “highly sensitive high-affinity-AHR” mice and cause a chain-reaction of events in the cell, when compared to the AHR in “highly resistant poor-affinity-AHR” mice. The Nebert laboratory in 1993 reported that these results can be explained by a small difference in the Ahr gene (mutation in the DNA) between the two kinds of mice. One of many chain-reaction events in the cell is the induction of enzymes called CYP1A1, CYP1A2 and CYP1B1. These enzymes can transform BaP (as well as other foreign chemicals, plus unknown compounds that are naturally-occurring in the cell) to reactive intermediates responsible for oxidative stress, inflammation and DNA damage (one or all of which appear to be responsible for toxicity or cancer to occur). However, after 30+ years of research on this topic, we can now conclude that CYP1A1 and CYP1A2 are far more beneficial than they are detrimental. For the past 3 or 4 decades, it has been widely known that CYP1 enzymes convert inert polycyclic aromatic hydrocarbons (PAHs) such as BaP into reactive intermediates. If pharmaceutical companies find that a candidate drug activates the AHR and induces the CYP1 enzymes, that drug is usually shelved for fear that it might cause toxicity or cancer. The CDC has worked on the problem of children eating PAHs including BaP from contaminated playgrounds. The findings from Cyp1(-/-) knockout mice have now turned these old ideas and concepts of fear upside down.
ASPET SURF Project Description: The ASPET SURF student(s) would engage in a contemporary facet of one of these two research topics within the research program areas that is most closely aligned to a pharmacology or toxicology focus and underpinning.  The specific research projects within the program areas described below evolve continuously. The ASPET SURF student would gain an understanding of evolutionary organization and selection of enzymes important to toxicology relevant to therapeutic (drugs) and environmental (toxicants) chemicals. The use of bio-assay and chemical assay methods would be incorporated into the ASPET SURF research project, as would exposure of contemporary methods of genetics including gene array technologies. Contemporary approaches to pharmacology and toxicology are the foundation of the ASPET SURF student’s research project experience. The ASPET SURF student who makes significant contributions to the research program would earn co-authorship and be expected to engage in experimental design and refinement, data collection and analysis, literature review and manuscript drafting and revision.