| Autor: |
Islam T; Department of Chemistry, University of Missouri, 125 Chemistry Building, Columbia, Missouri 65211, United States., Shim G; Department of Chemistry, University of Missouri, 125 Chemistry Building, Columbia, Missouri 65211, United States., Melton D; Department of Chemistry, University of Missouri, 125 Chemistry Building, Columbia, Missouri 65211, United States., Lewis CD; Department of Chemistry, University of Missouri, 125 Chemistry Building, Columbia, Missouri 65211, United States., Lei Z; University of Missouri, MU Metabolomics Center, 240f Christopher S. Bond Life Science Center, Columbia, Missouri 65211, United States., Gates KS; Department of Chemistry, University of Missouri, 125 Chemistry Building, Columbia, Missouri 65211, United States.; Department of Biochemistry, University of Missouri, 125 Chemistry Building, Columbia, Missouri 65211, United States. |
| Abstrakt: |
The clinically used antihypertensive agent hydralazine rapidly generates hydrazone-derived adducts by reaction with apurinic/apyrimidinic (also known as abasic or AP) sites in many different sequences of duplex DNA. The reaction rates are comparable to those of some AP-trapping reagents previously described as "ultrafast." Initially, reversible formation of a hydrazone adduct is followed by an oxidative cyclization reaction that generates a chemically stable triazolo[3,4- a ]phthalazine adduct. The net result is that the reaction of hydralazine with AP sites in duplex DNA yields a rapid and irreversible adduct formation. Although the hydrazone and triazolo[3,4- a ]phthalazine adducts differ by only two mass units, it was possible to use MALDI-TOF-MS and ESI-QTOF-nanospray-MS to quantitatively characterize mixtures of these adducts by deconvolution of overlapping isotope envelopes. Reactions of hydralazine with the endogenous ketone pyruvate do not prevent the formation of the hydralazine-AP adducts, providing further evidence that these adducts have the potential to form in cellular DNA. AP sites are ubiquitous in cellular DNA, and rapid, irreversible adduct formation by hydralazine could be relevant to the pathogenesis of systemic drug-induced lupus erythematosus experienced by some patients. Finally, hydralazine might be developed as a probe for the detection of AP sites, the study of cellular BER, and marking the location of AP sites in DNA-sequencing analyses. |
