Chemistry Home > Department Information > Faculty > Ian A. Blair

		Dr. Ian A. Blair - Professor of Pharmacology, Adjunct Professor of Chemistry
		BIOLOGICAL CHEMISTRY OFFICE: Room 1254, BRBII/III LAB: PHONE: (215) 573-9885 E-MAIL: ian@spirit.gcrc.upenn.edu EDUCATION AND ACADEMIC HISTORY: A.N. Richards Professor of Pharmacology Director of the Center for Cancer Pharmacology Vice-Chair, Department of Pharmacology University of Pennsylvania School of Medicine HONORS, AWARDS AND PROFESSIONAL ACTIVITIES: Norfolk County Major Award    (1964-1968) Fritzsche D. and O. Scholar (1968-1971) Royal Society of Chemistry Perkin Award (1980) Royal Society of Chemistry Travelling Fellowship (1982) Chair, Section on Quantitative Analysis American Society for Mass Spectrometry    (1985-1987) Ad hoc reviewer: NIH Metallobiochemistry Study Section (1990) Ad hoc reviewer: NIH Special Study Section, Pharmacological Sciences Program    (1990) Visiting Professorship, University of Kanazawa, Kanazawa, Japan (1991) NIH Metallobiochemistry Study Section (1992-1996) Ad hoc reviewer Metallobiochemistry Study Section (1998-1999) Ad hoc reviewer Division of Research Resources (1998-1999) American Society for Mass Spectrometry Program Committee (1998-2000) Editorial Board, Journal of Mass Spectrometry (1999-present) Editorial Board, Current    Drug Metabolism (1999-present) John Gilbert Memorial Lecture, Merck, West Point, PA (2000) Editorial Board: Chemical Research in Toxicology (2001-present) Ad hoc Reviewer Bioanalytical Engineering & Chemistry Review Panel (2002)

Research Summary Oxidative stress, carcinogenesis, and cardiovascular disease      The reactive oxygen species superoxide (O2-.), peroxide (O22-), and hydroxyl radical (HO.), are generated constantly in vivo from ground state triplet oxygen. This occurs by a variety of endogenous processes including, normal mitochondrial aerobic respiration, phagocytosis of bacteria or virus-containing cells, and peroxisomal-mediated degradation of fatty acids. Catechols, which arise in vivo through the metabolism of drugs, environmental chemicals, and endogenous hormones, generate reactive    oxygen species through redox cycling. The reactive oxygen species are normally detoxified by antioxidant defense systems such as, superoxide dismutase, catalase, reduced glutathione (GSH)-dependent peroxidases, and thioredoxin. Some of the    reactive oxygen species are able to escape these defenses in order to perform important metabolic roles. This means that there is always a potential for damage to lipids and macromolecules such as DNA and proteins, particularly in settings of oxidative stress. Lipid damage involves the formation of lipid hydroperoxides, which undergo homolytic decomposition to the a,b-unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal through two    quite distinct pathways. We have shown that one pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide and the other pathway involves the intermediate formation of another potential genotoxin, 4-hydroperoxy-2-nonenal. Lipid hydroperoxides can also be derived from the action of lipoxygenases and cyclooxygenases on polyunsaturated fatty acids. 4,5-Epoxy-2(E)-decenal forms    the unsubstituted etheno-2-deoxyadenosine adduct with DNA, a mutagenic lesion    which as been observed in human tissue DNA samples. Several new ethano- and    etheno-DNA-adducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. However, nothing is known about how these lesions affect proliferation or apoptosis. A role for 4-oxo-2-nonenal in the covalent modifications of proteins is also possible. 4-Hydroxy-2-nonenal forms propano adducts with 2'-deoxyguansine and also up-regulates cyclooxygenase-2 expression. As cyclooxygenase-2 converts linoleic acid into lipid hydroperoxides, this provides a potential mechanism for increased production of genotoxic bifunctional electrophiles. Our laboratory    is involved in determining the factors that control lipid hydroperoxide-mediated damage to DNA, RNA, and proteins. We are also characterizing the lesions in these macromolecules using novel mass spectrometry methodology, determining how the lesions affect proliferation and apoptosis using model in vitro systems, and assessing how such processes can be prevented using novel pharmacological agents. Selected Publications   Singh G, Xu K, Gutierrez A, Blair, IA: 2000. Liquid chromatography/electron capture atmospheric pressure chemical ionization/mass spectrometry: Analysis of pentafluorobenzyl    derivatives of biomolecules and drugs in the attomole range. Anal Chem 72:3007-3013. Lee, SH, Oe, T, Blair, IA: 2001. Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science, 292: 2083-2086. Pang, S, Zheng, N, Felix, CA, Scavuzzo, J, Boston, R, Blair, IA: 2001. Simultaneous determination of etoposide and its catechol metabolite in the plasma of pediatric patients    by liquid chromatography/tandem mass spectrometry." J. Mass Spectrom. 36:771-781. Lee, SH, Blair, IA: 2001. Oxidative DNA damage and cardiovascular disease. Trends Cardiovasc    Med 11:148-155. Lovett BD, Lo Nigro L, Rappaport EF, Blair IA, Osheroff N, Zheng N, Megonigal MD, Williams WR, Nowell PC, Felix CA: 2001. Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-t(4;11) translocation. Proc Natl Acad Sci USA. 98:9802-9807. Oe T, Tian    Y, O'Dwyer PJ, Roberts DW, Malone MD, Bailey CJ, Blair, IA: 2002. A validated    liquid chromatography/tandem mass spectrometry assay for cis-amminedichloro (2-methylpyridine)platinum(II) in human plasma ultrafiltrate. Anal Chem 74:591-599. Lee, SH, Oe, T, Blair, IA: 2002: 4,5-Epoxy-2(E)-decenal-induced formation of 1,N6-Etheno-2'-deoxyadenosine and 1,N2-etheno-2'-deoxyguanosine adducts. Chem Res Toxicol 15:300-304. Back to faculty page