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.