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Structure of adduct X, the last unknown of the six major DNA adducts of mitomycin C formed in EMT6 mouse mammary tumor cells.

Abstract
Treatment of EMT6 mouse mammary tumor cells with mitomycin C (MC) results in the formation of six major MC-DNA adducts. We identified the last unknown of these ("adduct X") as a guanine N(2) adduct of 2, 7-diaminomitosene (2,7-DAM), in which the mitosene is linked at its C-10 position to guanine N(2). The assigned structure is based on UV and mass spectra of adduct X isolated directly from the cells, as well as on its difference UV, second-derivative UV, and circular dichroism spectra, synthesis from [8-(3)H]deoxyguanosine, and observation of its heat stability. These tests were carried out using 17 microg of synthetic material altogether. The mechanism of formation of adduct X involves reductive metabolism of MC to 2,7-DAM, which undergoes a second round of reductive activation to alkylate DNA, yielding adduct X and another 2,7-DAM-guanine adduct (adduct Y), which is linked at guanine N7 to the mitosene. Adduct Y has been described previously. Adduct X is formed preferentially at GpC, while adduct Y favors the GpG sequence. In contrast to MC-DNA adducts, the 2,7-DAM-DNA adducts are not cytotoxic.
AuthorsY Palom, M F Belcourt, S M Musser, A C Sartorelli, S Rockwell, M Tomasz
JournalChemical research in toxicology (Chem Res Toxicol) Vol. 13 Issue 6 Pg. 479-88 (Jun 2000) ISSN: 0893-228X [Print] United States
PMID10858321 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antibiotics, Antineoplastic
  • Cross-Linking Reagents
  • DNA Adducts
  • DNA, Neoplasm
  • Mitomycin
Topics
  • Animals
  • Antibiotics, Antineoplastic (metabolism, pharmacology)
  • Chromatography, High Pressure Liquid
  • Cross-Linking Reagents (metabolism, pharmacology)
  • DNA Adducts (biosynthesis, chemistry)
  • DNA Damage (drug effects)
  • DNA, Neoplasm (chemistry, drug effects)
  • Female
  • Mammary Neoplasms, Animal
  • Mass Spectrometry
  • Mice
  • Mitomycin (metabolism, pharmacology)
  • Molecular Structure
  • Tumor Cells, Cultured

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