Vanderbilt University

Center in Molecular Toxicology

F Peter Guengerich, Ph.D.
f.guengerich@vanderbilt.edu
http://www.toxicology.mc.vanderbilt.edu/

Project Description

The NIEHS Center at Vanderbilt University has been in existence and continuously supported by the NIEHS since 1967. The scientific base is the Center in Molecular Toxicology, an interdepartmental unit of investigators drawn from several departments in the School of Medicine and the Department of Chemistry. Currently, there are 16 named Center Investigators in the program from the Departments of Biochemistry, Chemistry, Medicine, and Pathology. These Center Investigators lead the programs, and the influence of the Center is extended to a larger base at the institution and in the community through collaborations and sharing of expertise. Current Research Cores include (i) Enzymatic Oxidation and Conjugation, (ii) Oxidative Damage, (iii) DNA Damage and Mutagenesis, (iv) Mechanisms of Cell Signaling, and (v) Structural Biology. Each Research Core is led by a Center Investigator and involves projects of Center Investigators and others. Service Core Facilities include (i) NMR and Crystallography, (ii) Mass Spectrometry, (iii) Proteomics, (iv) Molecular Recognition, and (v) Cell Biology. Other units include Administrative, Director's Office, and New Investigators. The Center grant also supports a Pilot Project program, seminars and symposia, and other items aimed at strengthening programs at Vanderbilt relevant to environmental health science research. During the current grant period, four Center Investigators were recruited to Vanderbilt. A strong toxicology training program is in place. Major interactions at Vanderbilt involve the Division of Clinical Pharmacology, the Vanderbilt-Ingram Cancer Center, the Clinical Nutrition Research Unit, and other programs. The overall focus of the NIEHS Center at Vanderbilt is basic chemical and biological aspects of molecular toxicology, with an emphasis on relevance to human health.

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Program Highlights

Mechanisms Involved in DNA Damage and Genetic Stability

A long-standing interest in the Vanderbilt Center has been the mechanisms in which DNA is damaged and the biochemical responses. DNA damage occurs with both exogenous and endogenous chemicals. Responses include mutation, repair, and signaling of biological responses to cells. These events are important not only with regard to cancer but also aging, teratology, and cardiovascular diseases.

The research in this area is supported by a number of NIH R01 grants and a program project (P01 ES05355, M. Stone, P.I.). The research is heavily dependent on some of the facility cores in the Center, particularly Mass Spectrometry and NMR & Crystallography. Center Investigators involved in this research include Drs. Burk, Cortez, Egli, Guengerich, Harris, Marnett, Pietenpol, Rizzo, and Stone. Investigators in this area have regular meetings to discuss research, and the program is very collaborative. Some collaborations are with other institutions.

The research covers a wide variety of facets of the research field ranging from chemistry to cell biology and utilizes sophisticated approaches including mass spectrometry, NMR spectrometry, X-ray crystallography, transient-state kinetics, and various biological methods. In the past year and a half, more than 20 X-ray crystal structures of DNA-DNA polymerase complexes have been solved.

Choi JY, Stover JS, Angel KC, Chowdhury G, Rizzo CJ, Guengerich FP. Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase eta selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site. J Biol Chem. 2006 281: 25297-306.

Otteneder MB, Knutson CG, Daniels JS, Hashim M, Crews BC, Remmel RP, Wang H, Rizzo C, Marnett LJ. In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M1dG. Proc Natl Acad Sci U S A. 2006 103: 6665-9.

Wang F, DeMuro NE, Elmquist CE, Stover JS, Rizzo CJ, Stone MP. Base-displaced intercalated structure of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in the recognition sequence of the NarI restriction enzyme, a hotspot for -2 bp deletions. J Am Chem Soc. 2006 128: 10085-95.

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Clinical Aspects of Oxidative Stress

One area of concentrated interest in the Center is research on oxidative stress. Oxidative stress is hypothesized to be a factor in many environmental health issues, and the translational research is linked to important basic research in this Center. Some of the clinical research is supported by a program project grant (P01 ES13125, N. Porter, P.I.), R01 grants from several NIH institutes, and the Center’s Integrative Health Sciences Facility Core. Center Investigators involved in the translational research include Drs. Aschner, Brown, Burk, Hartert, Ikizler, Marnett, Morrow, and Porter.

These studies also involve scientists at other institutions, including several NIEHS core centers and are directed toward roles of oxidative stress in a variety of disease states including neurotoxicity, renal, cardiovascular, pulmonary, cancer, and others.

Yin H, Gao L, Tai HH, Murphey LJ, Porter NA, Morrow JD. Urinary prostaglandin F2alpha is generated from the isoprostane pathway and not the cyclooxygenase in humans. J Biol Chem. 2007 282: 329-336.

Davis TA, Gao L, Yin H, Morrow JD, Porter NA. In vivo and in vitro lipid peroxidation of arachidonate esters: the effect of fish oil omega-3 lipids on product distribution. J Am Chem Soc. 2006 128: 14897-904.

Burk RF, Norsworthy BK, Hill KE, Motley AK, Byrne DW. Effects of chemical form of selenium on plasma biomarkers in a high-dose human supplementation trial. Cancer Epidemiol Biomarkers Prev. 2006 15: 804-10.

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