title: Depurinating naphthalene-DNA adducts in mouse skin related to cancer initiation.
abstract: Naphthalene has been shown to be a weak carcinogen in rats. To investigate its mechanism of metabolic activation and cancer initiation, mice were topically treated with naphthalene or one of its metabolites, 1-naphthol, 1,2-dihydrodiolnaphthalene (1,2-DDN), 1,2-dihydroxynaphthalene (1,2-DHN), and 1,2-naphthoquinone (1,2-NQ). After 4 h, the mice were sacrificed, the treated skin was excised, and the depurinating and stable DNA adducts were analyzed. The depurinating adducts were identified and quantified by ultraperformance liquid chromatography/tandem mass spectrometry, whereas the stable adducts were quantified by (32)P-postlabeling. For comparison, the stable adducts formed when a mixture of the four deoxyribonucleoside monophosphates was treated with 1,2-NQ or enzyme-activated naphthalene were also analyzed. The depurinating adducts 1,2-DHN-1-N3Ade and 1,2-DHN-1-N7Gua arise from reaction of 1,2-NQ with DNA. Similarly, the major stable adducts appear to derive from the 1,2-NQ. The depurinating DNA adducts are, in general, the most abundant. Therefore, naphthalene undergoes metabolic activation to the electrophilic ortho-quinone, 1,2-NQ, which reacts with DNA to form depurinating adducts. This is the same mechanism as other weak carcinogens, such as the natural and synthetic estrogens, and benzene.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Saeed
authors.forename: Sheila
authors.initials: S
authors.lastname: Higginbotham
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gaikwad
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Chakravarti
authors.forename: Eleanor
authors.initials: E
authors.lastname: Rogan
authors.forename: Ercole
authors.initials: E
authors.lastname: Cavalieri
mesh_terms: D000818:Animals; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018632:Mice, Inbred SENCAR; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology*
chemical_list: D018736:DNA Adducts; D009281:Naphthalenes; C031721:naphthalene