Home > Faculty > Primary > Blair

Department of Pharmacology
Ian A. Blair, Ph.D.

Education:

1968	BSc (Chemistry)	University of London
1968	ARCS	Royal College of Science
1971	DIC	Imperial College of Science and Technology
1971	Ph.D. (Organic Chemistry)	University of London (Advisor, Nobel Laureate Sir Derek HR Barton)
1997	MA (Honorary)	University of Pennsylvania

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, peroxide, and hydroxyl radical, 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 proteins, peptides, and DNA, 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, 4,5-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 arachidonic 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 oxidative stress-mediated damage to proteins, peptides and DNA. We are quantifying these modified proteins, peptides, and DNA together with selected endogenous metabolites using novel mass spectrometry methodology to act as biomarkers for assessing whether such processes occur in cardiovascular disease and cancer. We are also determining whether their formation can be prevented using novel pharmacological agents.