Synthesis and characterization of polycyclic aromatic hydrocarbon o-quinone depurinating N7-guanine adducts

Chem Res Toxicol. 1999 Mar;12(3):237-46. doi: 10.1021/tx980182z.

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants which may cause cancer and require metabolic activation to exert their carcinogenic effects. One pathway of activation involves the dihydrodiol dehydrogenase-catalyzed oxidation of non-K region trans-dihydrodiols to yield catechols, which autoxidize to form reactive o-quinones. As a step toward identifying the spectrum of PAH o-quinone-DNA adducts that may form in biological systems, depurinating PAH o-quinone-guanine adducts were synthesized. Naphthalene-1,2-dione, phenanthrene-1,2-dione, and benzo[a]pyrene-7, 8-dione were reacted with 5 equiv of 2'-deoxyguanosine (dGuo) under acidic conditions (1:1 acetic acid/water). The products were purified by reversed-phase HPLC, characterized by a combination of UV spectroscopy, electrospray ionization/tandem mass spectrometry, and high-field proton nuclear magnetic resonance spectroscopy, and identified as 7-(naphthalene-1,2-dion-4-yl)guanine (MH+, m/z 308), 7-(phenanthrene-1,2-dion-4-yl)guanine (MH+, m/z 358), and 7-(benzo[a]pyrene-7,8-dion-10-yl)guanine (MH+, m/z 432), respectively. Reaction at N7 of dGuo leads to cleavage of the glycosidic bond, producing depurinating adducts. Reaction of phenanthrene-1,2-dione with calf thymus DNA led to the formation of the corresponding depurinating adduct. The loss of modified bases in DNA generates apurinic sites which, if unrepaired, can lead to mutations and thus cellular transformation. These synthesized PAH o-quinone-N7-guanine adducts can be used as standards to identify such adducts in vitro and in vivo.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzopyrenes / chemistry*
  • Cattle
  • Chromatography, High Pressure Liquid
  • DNA Adducts / chemical synthesis*
  • Deoxyguanosine / chemistry*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Naphthalenes / chemistry*
  • Phenanthrenes / chemistry*
  • Spectrophotometry, Ultraviolet

Substances

  • Benzopyrenes
  • DNA Adducts
  • Naphthalenes
  • Phenanthrenes
  • naphthalene-1,2-dione
  • 1,2-phenanthrenequinone
  • benzo(a)pyrene-7,8-dione
  • Deoxyguanosine