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Ian A. Blair, Ph.D. A. N. Richards Professor of Pharmacology Professor of Chemistry Director, Program in Systems Biology, ITMAT Director, Center for Cancer Pharmacology Vice-Chair, Department of Pharmacology Scientific Director, Abramson Cancer Center and the Penn Genomics Institute Proteomics Facilities Member, Graduate Group in Pharmacological Sciences Department of Pharmacology |
| Education: | 1968 | BSc (Chemistry) | University of London |
| 1968 | ARCS | Royal College of Science | |
| 1971 | DIC | Imperial College of Science and Technology | |
| 1971 | PhD (Organic Chemistry) | University of London (1971; Advisor, Nobel Laureate Sir Derek HR Barton) | |
| 1997 | MA (honorary) | University of Pennsylvania |
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Research Summary: Research in the Blair laboratory is heavily involved in the use of mass spectrometry for proteomics and DNA analysis. 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 aldehydic genotoxins, 4-oxo-2-nonenal, 4-hydroperoxy-2(E)-decenal, and 4-hydroxy-2-nonenal. The 4-hydroperoxy-2(E)-nonenal, which is the immediate precursor of 4-oxo-2(E)-nonenal and 4-hydroxy-2(E)-nonenal, is also responsible for formation of unsubstituted etheno-DNA-adducts. These mutagenic lesions have 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. We have now demonstrated that 4-oxo-2(E)-nonenal induces apoptosis in endothelial cells and forms a unique cyclic glutathione adduct. Using in vitro models we have recently demonstrated that this adduct is formed endogenously and that it provides a novel biomarker of oxidative stress. These studies also revealed that an isomer of 4-hydroxy-2-nonenal, 4-hydroxy-2(E)-nonenol can be formed intracellularly through reduction of 4-oxo-2(E)-nonenal. We are now evaluating the role that this isomer plays in oxidative stress and damage to cellular macromolecules. Our laboratory is involved in determining the factors that control lipid hydroperoxide-mediated damage to DNA, RNA, and proteins. We are characterizing the lesions in these macromolecules using novel mass spectrometry methodology and determining how the lesions affect proliferation and apoptosis in in vitro systems and in animal models. We are also developing novel therapeutic agents that modulate apoptosis as possible anticancer therapies. Selected Key Publications: Singh G, Xu K, Gutierrez A & Blair IA: 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, 2000. Lee SH, Oe T & Blair IA: Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science 292: 2083-2086, 2001. Lee SH & Blair IA: Oxidative DNA damage and cardiovascular disease. Trends Cardiovasc Med 11: 148-155, 2001.
Oe T, Tian Y, O'Dwyer PJ, Roberts DW, Malone MD, Bailey CJ & Blair IA: Determination of the platinum drug cis-amminedichloro(2-methylpyridine) platinum(II) in human urine by liquid chromatography-tandem mass spectrometry. Lee, SH, Oe, T, Blair, IA: 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, 2002. Blair IA & Tilve A: Analysis of anticancer drugs and their metabolites by mass spectrometry. Curr Drug Metab 3: 463-480, 2002. Pollack M, Oe T, Lee SH, Silva Elipe MV, Arison BH & Blair IA: Characterization of 2'-deoxycytidine adducts derived from 4-oxo-2nonenal, a novel lipid peroxidation product. Chem Res Toxicol 16: 893-900, 2003. Lee SH, Williams MV, DuBois RN & Blair IA: Targeted lipidomics using electron capture atmospheric pressure chemical ionization mass spectrometry. Rapid Commun Mass Spectrom 17: 2168-2176, 2003. Oe T, Arora JS, Lee SH & Blair IA: A novel lipid hydroperoxide derived cyclic covalent modification to Histone H4. J Biol Chem 278: 42098-105, 2003. Oe T, Lee SH, Elipe MV, Arison BH & Blair IA: A novel lipid hydroperoxide-derived modification to arginine. Chem Res Toxicol 16: 1598-1605, 2003. Zhuo X, Zheng N, Felix CA & Blair IA: Kinetics and regulation of cytochrome P450-mediated etoposide metabolism Drug Metab Dispos 32: 993-1000, 2004. Szewczuk LM, Lee SH, Blair IA & Penning TM: Viniferin formation by COX-1: evidence for radical intermediates during co-oxidation of resveratrol. J Nat Prod 68: 36-42, 2005. Williams MV, Lee S-H & Blair IA: Liquid chromatography/mass spectrometry analysis of bifunctional electrophiles and DNA adducts from vitamin C mediated decomposition of 15-hydroperoxyeicosatetraenoic acid. Rapid Commun Mass Spectrom 19: 849-858, 2005. Lee SH, Silva Elipe MV, Arora JS & Blair IA: Dioxododecenoic acid: a lipid hydroperoxide-derived bi-functional electrophile responsible for etheno DNA-adduct formation. Chem Res Toxicol 18: 566-578, 2005. Lee SH, Arora JA, Oe T & Blair IA: 4-Hydroperoxy-2-nonenal-induced formation of 1,N(2)-etheno-2'-deoxyguanosine adducts. Chem Res Toxicol 18: 780-786, 2005. Jian W, Lee SH, Arora JS & Blair IA: Unexpected formation of etheno-2'-deoxyguanosine adducts from 5(S)-hydroperoxyeicosatetraenoic acid: Evidence for a bis-hydroperoxide intermediate. Chem Res. Toxicol 18: 599-610, 2005. Lee SH, Oe T, Arora JS & Blair IA: Analysis of FeII-mediated decomposition of linoleic acid-derived lipid hydroperoxide by lipid chromatography/mass spectrometry. J Mass Spectrom 40: 661-668, 2005. Mistry AR, Felix CA, Whitemarsh RJ, Mason A, Reiter A, Cassinat B, Parry A, Walz C, Wiemels JL, Segal MR, Ades L, Blair IA, Osheroff N, Peniket AJ, Lafage-Pochitaloff M, Cross NCP, Chomienne C, Solomon E, Fenaux P & Grimwade D: DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 352: 1529-1538, 2005. Yocum AK, Oe T, Yergey AL & Blair IA: Novel lipid hydroperoxide-derived hemoglobin histidine adducts as biomarkers of oxidative stress. J Mass Spectrom 40: 754-764, 2005. Lee SH, Williams MV, DuBois RN & Blair IA: Cyclooxygenase-2-mediated DNA damage. J Biol Chem 280: 28337-28346, 2005. Jian W; Arora JS; Oe T, Shuvaev VV & Blair IA: Induction of endothelial cell apoptosis by lipid hydroperoxide-derived bifunctional electrophiles. Free Radic Biol Med In Press, 2005. Yocum, A.K., Yu, K.H., Oe, T., Blair, I.A. "Effect of immunoaffinity depletion of human serum during proteomic investigations." J. Proteome Res. 4:1722-31, 2005. Yu, K.H., Rustgi, A.K., Blair, I.A. "Characterization of proteins in human pancreatic cancer serum using differential gel electrophoresis and tandem mass spectrometry." J. Proteome Res. 4:1742-51, 2005. Yan, Y., Weaver, V.M., & Blair, I.A. "Analysis of protein expression during oxidative stress in breast epithelial cells using a stable isotope labeled proteome internal standard." J. Proteome Res. 4:2007-14, 2005. Inoue, K., Garner, C., Ackermann, B.L., Oe, T., Blair, I.A. "Liquid chromatography/tandem mass spectrometry characterization of oxidized amyloid beta peptides as potential biomarkers of Alzheimer's disease." Rapid Commun. Mass Spectrom. 20:911-918, 2006. Williams, M. V., Lee, S.H., Pollack, M., and Blair, I.A. "Endogenous lipid hydroperoxide-mediated DNA-adduct formation in min mice" J Biol Chem 281(15):10127-33, . 2006. Ruan,Q., Kim H-Y, Hao J, Penning T, Harvey R, Blair IA. Quantification of benzo[a]pyrene diol epoxide DNA-adducts by stable isotope dilution liquid chromatography-tandem mass spectrometry. Rapid Commun. Mass Spectrom. 20:1369-1380, 2006. Awards, Honors, Membership in Honorary Societies:
Institute for Translational Medicine and Therapeutics 841 Biomedical Research Building II/III University of Pennsylvania 421 Curie Blvd. Philadelphia, PA 19104-6160 Lab Telephone: 215-573-9886, 9878 Lab Fax: 215-573-9889 Links:http://www.med.upenn.edu/ccp/ http://www.med.upenn.edu/ccp/blair_lab/index.shtml http://www.sas.upenn.edu/chem/ |
