TY - JOUR
T1 - Depurinating naphthalene-DNA adducts in mouse skin related to cancer initiation
AU - Saeed, Muhammad
AU - Higginbotham, Sheila
AU - Gaikwad, Nilesh
AU - Chakravarti, Dhrubajyoti
AU - Rogan, Eleanor
AU - Cavalieri, Ercole
N1 - Funding Information:
This research was supported by U.S. Public Health Service Grant P01 CA49210. Core support at the Eppley Institute was provided by Grant P30 CA36727 from the National Cancer Institute.
PY - 2009/10/1
Y1 - 2009/10/1
N2 - 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.
AB - 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.
KW - 1,2-Naphthalene quinone ultimate carcinogenic metabolite
KW - Depurinating naphthalene-DNA adducts
KW - Metabolic activation of naphthalene
KW - Naphthalene
KW - Stable naphthalene-DNA adducts
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U2 - 10.1016/j.freeradbiomed.2009.07.020
DO - 10.1016/j.freeradbiomed.2009.07.020
M3 - Article
C2 - 19619639
AN - SCOPUS:69249210944
SN - 0891-5849
VL - 47
SP - 1075
EP - 1081
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 7
ER -