Depurinating naphthalene-DNA adducts in mouse skin related to cancer initiation

Muhammad Saeed, Sheila Higginbotham, Nilesh Gaikwad, Dhrubajyoti Chakravarti, Eleanor Rogan, Ercole Cavalieri

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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 32P-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.

Original languageEnglish (US)
Pages (from-to)1075-1081
Number of pages7
JournalFree Radical Biology and Medicine
Volume47
Issue number7
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

Keywords

  • 1,2-Naphthalene quinone ultimate carcinogenic metabolite
  • Depurinating naphthalene-DNA adducts
  • Metabolic activation of naphthalene
  • Naphthalene
  • Stable naphthalene-DNA adducts

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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