Synthesis and structure determination of 6-methylbenzo[a]pyrene- deoxyribonucleoside adducts and their identification and quantitation in vitro and in mouse skin

Aaron A. Hanson, Kai Ming Li, Cheng Huang Lin, Ryszard Jankowiak, Gerald J. Small, Eleanor G Rogan, Ercole Cavalieri

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)65-90
Number of pages26
JournalChemico-Biological Interactions
Volume128
Issue number1
DOIs
StatePublished - Aug 15 2000

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Deoxyribonucleosides
Cations
Skin
Aromatic Hydrocarbons
Oxidation
DNA Adducts
DNA
Guanine
Liver Microsomes
Horseradish Peroxidase
Metabolites
Iodine
Carcinogens
Liver
Rats
Tumors
Chemical activation
High Pressure Liquid Chromatography
Electrons
6-methylbenzo(a)pyrene

Keywords

  • 6-Methylbenzo[a]pyrene-deoxyribonucleoside adducts
  • Carcinogen
  • Mouse skin

ASJC Scopus subject areas

  • Toxicology

Cite this

Synthesis and structure determination of 6-methylbenzo[a]pyrene- deoxyribonucleoside adducts and their identification and quantitation in vitro and in mouse skin. / Hanson, Aaron A.; Li, Kai Ming; Lin, Cheng Huang; Jankowiak, Ryszard; Small, Gerald J.; Rogan, Eleanor G; Cavalieri, Ercole.

In: Chemico-Biological Interactions, Vol. 128, No. 1, 15.08.2000, p. 65-90.

Research output: Contribution to journalArticle

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title = "Synthesis and structure determination of 6-methylbenzo[a]pyrene- deoxyribonucleoside adducts and their identification and quantitation in vitro and in mouse skin",
abstract = "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.",
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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

PY - 2000/8/15

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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.

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