Synthesis, characterization, and 32p-postlabeling analysis of DNA adducts derived from the environmental contaminant 3-nitrobenzanthrone

Chem Res Toxicol. 2005 Jun;18(6):1056-70. doi: 10.1021/tx0500474.

Abstract

3-Nitrobenzanthrone (3-NBA) is a potent mutagen and potential human carcinogen identified in diesel exhaust and ambient air particulate matter. 3-NBA forms DNA adducts in rodent tissues that arise principally through reduction to N-hydroxy-3-aminobenzanthrone (N-OH-ABA), esterification to its acetate or sulfate ester, and reaction of this activated ester with DNA. We detected 3-NBA-derived DNA adducts in rodent tissues by (32)P-postlabeling and generated them chemically by acid-catalyzed reaction of N-OH-ABA with DNA, but their structural identification has not yet been reported. We have now prepared 3-NBA-derived adducts by reaction of a possible reactive metabolite, N-acetoxy-N-acetyl-3-aminobenzanthrone (N-Aco-N-Ac-ABA), with purine nucleosides and nucleotides, characterized them, and have shown that they are present in DNA treated with this 3-NBA derivative. Three of these adducts have been characterized as the C-C adduct N-acetyl-3-amino-2-(2'-deoxyguanosin-8-yl)benzanthrone, the C-N adduct N-acetyl-N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone, and an unusual 3-acetylaminobenzanthrone adduct of deoxyadenosine, which involves a double linkage between adenine and benzanthrone (N1 to C1, N(6) to C11b), creating a five-membered imidazo type ring system. According to IUPAC fused ring conventions, we propose the following systematic name for this adduct: (9'-(2' '-deoxyribofuranosyl))purino[6',1':2,3]imidazo[5,4-p](1,11b-dihydro-(N-acetyl-3-amino))benzanthrone. The 3'-phosphates of these novel adducts could be 5'-postlabeled using [gamma-(32)P]ATP, although the efficiency of labeling was found to be low (less than 20%). However, none of these adducts could be detected in DNA from 3-NBA-treated rats by (32)P-postlabeling. Two of these synthetic adducts were treated with alkali to generate nonacetylated adducts, and these were also shown by HPLC to differ from those adducts found in rat DNA. Therefore, a different approach to the synthesis of authentic standards is needed for the structural characterization of 3-NBA-derived DNA adducts formed in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benz(a)Anthracenes / chemistry
  • Benz(a)Anthracenes / metabolism
  • Benz(a)Anthracenes / toxicity*
  • Chromatography, High Pressure Liquid
  • DNA / chemistry
  • DNA / drug effects*
  • DNA / metabolism
  • DNA Adducts / chemistry
  • DNA Adducts / drug effects*
  • DNA Adducts / metabolism
  • DNA Damage
  • Environmental Pollutants / metabolism
  • Environmental Pollutants / toxicity*
  • Female
  • Molecular Structure
  • Phosphorus Radioisotopes
  • Rats
  • Rats, Wistar

Substances

  • Benz(a)Anthracenes
  • DNA Adducts
  • Environmental Pollutants
  • Phosphorus Radioisotopes
  • DNA
  • 3-nitrobenzanthrone