TY - JOUR
T1 - Synthesis and structure determination of 6-methylbenzo[a]pyrene- deoxyribonucleoside adducts and their identification and quantitation in vitro and in mouse skin
AU - Hanson, Aaron A.
AU - Li, Kai Ming
AU - Lin, Cheng Huang
AU - Jankowiak, Ryszard
AU - Small, Gerald J.
AU - Rogan, Eleanor G.
AU - Cavalieri, Ercole L.
N1 - Funding Information:
We gratefully thank Dr. Ronald Cerny at the Nebraska Center for Mass Spectrometry at the University of Nebraska-Lincoln for the valuable mass spectral data. We extend our deepest gratitude to Paula Mailander and Dr. Dhruba Chakravarti for help in isolating DNA from 6-CH 3 BP-7,8-dihydrodiol-treated mouse skin. We would also like to thank Sheila Higginbotham for her help with the mouse skin experiments. This research was supported by a US PHS grant from the National Cancer Institute (P01 CA49210). Core support at the Eppley Institute was funded by NCI Laboratory Cancer Research Center Support (Core) Grant CA36727. Aaron Hanson received fellowship support from the Eppley Institute, the University of Nebraska Center for Environmental Toxicology and the University of Nebraska Medical Center.
PY - 2000/8/15
Y1 - 2000/8/15
N2 - Activation of the moderate carcinogen 6-methylbenzo[a]pyrene (6-CH3BP) by one-electron oxidation to form DNA adducts was studied. Iodine oxidation of 6-CH3BP in the presence of dGuo produces BP-6-CH2-N2dGuo, BP-6-CH2- N7Gua and a mixture of 6-CH3BP-(1 and 3)-N7Gua, whereas in the presence of Ade the adducts BP-6-CH2-N1Ade, BP-6-CH2-N3Ade, BP-6-CH2-N7Ade and 6- CH3BP-(1 and 3)-N1Ade are obtained. Furthermore, for the first time an aromatic hydrocarbon radical cation afforded an adduct with dThd, the stable adduct BP-6-CH2-N3dThd. Formation of these adducts indicates that the 6- CH3BP radical cation has charge localized at the 6, 1 and 3 position. When 6-CH3BP was activated by horseradish peroxidase in the presence of DNA, two depurinating adducts were identified, BP-6-CH2-N7Gua (48%) and 6-CH3BP-(1 and 3)-N7Gua (23%), with 29% unidentified stable adducts. In the binding of 6-CH3BP catalyzed by rat liver microsomes, the same two depurinating adducts, BP-6-CH2-N7Gua (22%) and 6-CH3BP-(1 and 3)-N7Gua (10%), were identified, with 68% unidentified stable adducts. In 6-CH3BP-treated mouse skin, the two depurinating adducts, BP-6-CH2-N7Gua and 6-CH3BP-(1 and 3)- N7Gua, were identified. Although quantitation of these two adducts was not possible due to coelution of metabolites on HPLC, they appeared to be the major adducts found in mouse skin. These results show that 6-CH3BP forms depurinating adducts only with the guanine base of DNA, both in vitro and in mouse skin. The weaker reactivity of 6-CH3BP radical cation vs. BP radical cation could account for the weaker tumor-initiating activity of 6-CH3BP in comparison to that of BP. (C) 2000 Elsevier Science Ireland Ltd.
AB - Activation of the moderate carcinogen 6-methylbenzo[a]pyrene (6-CH3BP) by one-electron oxidation to form DNA adducts was studied. Iodine oxidation of 6-CH3BP in the presence of dGuo produces BP-6-CH2-N2dGuo, BP-6-CH2- N7Gua and a mixture of 6-CH3BP-(1 and 3)-N7Gua, whereas in the presence of Ade the adducts BP-6-CH2-N1Ade, BP-6-CH2-N3Ade, BP-6-CH2-N7Ade and 6- CH3BP-(1 and 3)-N1Ade are obtained. Furthermore, for the first time an aromatic hydrocarbon radical cation afforded an adduct with dThd, the stable adduct BP-6-CH2-N3dThd. Formation of these adducts indicates that the 6- CH3BP radical cation has charge localized at the 6, 1 and 3 position. When 6-CH3BP was activated by horseradish peroxidase in the presence of DNA, two depurinating adducts were identified, BP-6-CH2-N7Gua (48%) and 6-CH3BP-(1 and 3)-N7Gua (23%), with 29% unidentified stable adducts. In the binding of 6-CH3BP catalyzed by rat liver microsomes, the same two depurinating adducts, BP-6-CH2-N7Gua (22%) and 6-CH3BP-(1 and 3)-N7Gua (10%), were identified, with 68% unidentified stable adducts. In 6-CH3BP-treated mouse skin, the two depurinating adducts, BP-6-CH2-N7Gua and 6-CH3BP-(1 and 3)- N7Gua, were identified. Although quantitation of these two adducts was not possible due to coelution of metabolites on HPLC, they appeared to be the major adducts found in mouse skin. These results show that 6-CH3BP forms depurinating adducts only with the guanine base of DNA, both in vitro and in mouse skin. The weaker reactivity of 6-CH3BP radical cation vs. BP radical cation could account for the weaker tumor-initiating activity of 6-CH3BP in comparison to that of BP. (C) 2000 Elsevier Science Ireland Ltd.
KW - 6-Methylbenzo[a]pyrene-deoxyribonucleoside adducts
KW - Carcinogen
KW - Mouse skin
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U2 - 10.1016/S0009-2797(00)00189-7
DO - 10.1016/S0009-2797(00)00189-7
M3 - Article
C2 - 10996301
AN - SCOPUS:0034662756
SN - 0009-2797
VL - 128
SP - 65
EP - 90
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 1
ER -