A unifying goal for this research is to understand the mechanisms of fragmentations so that interpretations of production-ion spectra can be placed on a firm foundation. Therefore, the first aim is to evaluate various spectrometry methods to distinguish isomeric adducts and potential biomarkers. New to our effort will be a major activity to understand isomerically distinct fragmentations by using molecular orbital calculations. Six classes of fragmentations are identified for study on the basis of our experience in this area. In parallel with developing an understanding of ion chemistry, we will develop and validate electrospray liquid chromatography (LC/MS) and LC-tandem-MS methods for the trace determination of estrogen metabolites, conjugates, and nucleobase adducts. We are proposing two approaches: a low-throughput method that posses maximal certainty for identification of analytes and a high- throughput method for rapid screening of tissues. These methods will then be used to support research in other subprojects. Emphasis will be on analysis of tissues for estrogen biomarkers and on biological fluids for polycyclic aromatic hydrocarbon (PAH) adducts. We will also emphasize a biophysical aspect of MS in which the instrumentation is used to evaluate the binding of carcinogens to DNA by investigating non- covalent complexes of small duplex oligodeoxynucleotides and estrogens or PAH. Following the study of interactions, we focus on the modification reactions themselves by devising and utilizing MS methods for following directly the reactions of carcinogens with model single and double-stranded oligonucleotides. Sufficient preliminary results support the launch of these latter, relatively new projects.
| Cavalieri, Ercole; Saeed, Muhammad; Zahid, Muhammad et al. (2012) Mechanism of DNA depurination by carcinogens in relation to cancer initiation. IUBMB Life 64:169-79 |
| Zahid, Muhammad; Saeed, Muhammad; Rogan, Eleanor G et al. (2010) Benzene and dopamine catechol quinones could initiate cancer or neurogenic disease. Free Radic Biol Med 48:318-24 |
| Saeed, Muhammad; Rogan, Eleanor; Cavalieri, Ercole (2009) Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: the defining link to natural estrogens. Int J Cancer 124:1276-84 |
| Saeed, Muhammad; Higginbotham, Sheila; Gaikwad, Nilesh et al. (2009) Depurinating naphthalene-DNA adducts in mouse skin related to cancer initiation. Free Radic Biol Med 47:1075-81 |
| Lu, Fang; Zahid, Muhammad; Wang, Cheng et al. (2008) Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev Res (Phila Pa) 1:135-45 |
| Gaikwad, Nilesh W; Yang, Li; Muti, Paola et al. (2008) The molecular etiology of breast cancer: evidence from biomarkers of risk. Int J Cancer 122:1949-57 |
| Chakravarti, Dhrubajyoti; Venugopal, Divya; Mailander, Paula C et al. (2008) The role of polycyclic aromatic hydrocarbon-DNA adducts in inducing mutations in mouse skin. Mutat Res 649:161-78 |
| Zahid, Muhammad; Saeed, Muhammad; Lu, Fang et al. (2007) Inhibition of catechol-O-methyltransferase increases estrogen-DNA adduct formation. Free Radic Biol Med 43:1534-40 |
| Gaikwad, Nilesh W; Rogan, Eleanor G; Cavalieri, Ercole L (2007) Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic Biol Med 43:1289-98 |
| Zahid, Muhammad; Gaikwad, Nilesh W; Rogan, Eleanor G et al. (2007) Inhibition of depurinating estrogen-DNA adduct formation by natural compounds. Chem Res Toxicol 20:1947-53 |
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