Formation of Depurinating N3adenine and N7guanine Adducts After Reaction of 1,2-naphthoquinone or Enzyme-Activated 1,2-dihydroxynaphthalene With DNA. Implications for the Mechanism of Tumor Initiation by Naphthalene

Chem Biol Interact. 2007 Feb 20;165(3):175-88. doi: 10.1016/j.cbi.2006.12.007. Epub 2006 Dec 16.

Abstract

Naphthalene is considered by the US Environmental Protection Agency to be a carcinogenic compound based on inhalation studies in rats. The primary metabolite of naphthalene is naphthalene 1,2-arene oxide. This unstable intermediate can lead to formation of 1-naphthol and naphthalene-1,2-dihydrodiol. Secondary metabolites include 1,2-dihydroxynaphthalene (1,2-DHN), which can be further oxidized to 1,2-naphthoquinone (1,2-NQ). Based on the metabolism of naphthalene and its similarity to the metabolic activation of carcinogenic natural estrogens, synthetic estrogens and benzene, we hypothesize that naphthalene is activated to initiate cancer by reaction of 1,2-NQ with DNA to form the depurinating adducts 1,2-DHN-4-N3Ade and 1,2-DHN-4-N7Gua. These adducts were synthesized by reaction of 1,2-NQ with Ade or dG in acetic acid/water/DMF (1:1:1). 1,2-NQ was reacted with DNA, and the depurinating 1,2-DHN-4-N3Ade and 1,2-DHN-4-N7Gua adducts were analyzed by ultraperformance liquid chromatography/tandem mass spectrometry and HPLC with electrochemical detection. After the reaction of 1,2-NQ with DNA, the N3Ade and N7Gua adducts were found. Similarly, when 1,2-DHN was activated by tyrosinase in the presence of DNA, higher amounts of the N3Ade and N7Gua adducts were detected. These same adducts were also formed when 1,2-DHN was activated by prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. These depurinating adducts are analogous to those obtained from the ortho-quinones of natural estrogens, synthetic estrogens and benzene. These results suggest that reaction of ortho-quinones with DNA by 1,4-Michael addition is a general mechanism of weak carcinogenesis that occurs with naphthalene and a number of other aromatic compounds.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenine / chemistry*
  • Carcinogens / chemistry
  • Carcinogens / toxicity*
  • DNA Adducts / chemical synthesis*
  • DNA Adducts / chemistry
  • Guanine / chemistry*
  • Kinetics
  • Molecular Structure
  • Naphthalenes / chemistry
  • Naphthalenes / toxicity*
  • Naphthols / chemistry*
  • Naphthoquinones / chemistry*
  • Neoplasms / chemically induced
  • Neoplasms / genetics

Substances

  • Carcinogens
  • DNA Adducts
  • Naphthalenes
  • Naphthols
  • Naphthoquinones
  • naphthalene
  • 1,2-dihydroxynaphthalene
  • Guanine
  • 1,2-naphthoquinone
  • Adenine