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: Muhammad Saeed, Sheila Higginbotham, Nilesh Gaikwad, Dhrubajyoti Chakravarti, Eleanor Rogan, Ercole Cavalieri
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 47 Issue 7 Pg. 1075-81 (Oct 01 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19619639 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA Adducts
• Naphthalenes
• naphthalene

Topics

• Animals
• DNA Adducts (chemistry, metabolism)
• Mice
• Mice, Inbred SENCAR
• Naphthalenes (chemistry, metabolism, toxicity)
• Skin Neoplasms (chemically induced, pathology)