2004 Highlights

• "Radical" Damage and Human Disease
• P450 Enzymes: Ridding the Body of Toxins

"Radical" Damage and Human Disease
A long-term research focus of this Core Center has involved a process known as lipid peroxidation. Lipid peroxidation is the result of a cell membrane reacting with free radicals (rogue atoms that are highly reactive and destructive to delicate lipid-based cell membranes due to an odd number of electrons). This damage at the cellular level figures significantly in aspects of nutrition, various inflammatory diseases, and even cancer. One of the research areas in the Core Center, Oxidative Damage, focuses on several efforts, including important collaborations among Profs. Porter, Marnett, Rizzo, Burk, Caprioli, and Morrow. Studies in basic chemistry have led to a better understanding of the lipid peroxidation process itself and to the development of powerful antioxidants (dietary nutrients that help the body defend itself against oxidative damage). Some of these new antioxidants are more powerful than the naturally occurring antioxidant Vitamin E. Other work has led to improved analysis of the products created as a result of lipid peroxidation. An increased ability to identify lipid peroxidation when it occurs may supply the foundation for developing diagnostic tools for specific illnesses, including neurodegenerative and cardiovascular diseases and cancer. 



Selected Publications

• West JD, Ji C, Duncan ST, Amarnath V, Schneider C, Rizzo CJ, Brash AR, Marnett LJ. 2004 Apr. Induction of apoptosis in colorectal carcinoma cells treated with 4-hydroxy-2-nonenal and structurally related aldehydic products of lipid peroxidation. Chem Res Toxicol17 (4):453-62.
• Wijtmans M, Pratt DA, Valgimigli L, DiLabio GA, Pedulli GF, Porter NA. 2003 Sep 22. 6-Amino-3-pyridinols: towards diffusion-controlled chain-breaking antioxidants. Angew Chem Int Ed Engl42 (36):4370-3.
• Yin H, Morrow JD, Porter NA. 2004 Jan 30. Identification of a novel class of endoperoxides from arachidonate autoxidation. J Biol Chem279 (5):3766-76.

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P450 Enzymes: Ridding the Body of Toxins
Another long-term effort in this Center involves the cytochrome P450 enzymes, a group of enzymes responsible for enabling the body to deal with toxins. P450 research is conducted in the Enzymatic Oxidation and Conjugation Research Core by Profs. Guengerich, Keeney, and Waterman. The work involves chemical, physical, and biological studies on human P450 enzymes, as well as P450 found in certain animals and microbes. These studies are highly relevant to issues of metabolism and toxicity of xenobiotic chemicals (synthetic chemicals that do not occur naturally), as well as the role of these enzymes in processing endogenous chemicals (chemicals produced by the body itself). By gaining a grasp of P450 function and how different toxins are metabolized, researchers hope to identify the factors that lead to toxicity and disease.

Selected Publications

• Guengerich FP, Krauser JA, Johnson WW. 2004 Aug 24. Rate-limiting steps in oxidations catalyzed by rabbit cytochrome P450 1A2. Biochemistry43 (33):10775-88.
• Kim D, Guengerich FP. 2004 Feb 3. Selection of human cytochrome P450 1A2 mutants with enhanced catalytic activity for heterocyclic amine N-hydroxylation. Biochemistry43 (4):981-8.
• Podust LM, Yermalitskaya LV, Lepesheva GI, Podust VN, Dalmasso EA, Waterman MR. 2004 Nov. Estriol bound and ligand-free structures of sterol 14alpha-demethylase. Structure (Camb)12 (11):1937-45.

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