DNA Adduct Formation by Polycyclic Aromatic Hydrocarbon Dihydrodiol Epoxides

Szeliga, Jan; Dipple, Anthony

doi:10.1021/tx970142f

Cited by 204 publications

(227 citation statements)

References 49 publications

(94 reference statements)

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“…For 14, the absolute configuration of the pyridyl-substituted carbon was determined by reaction of chiral nornicotine with protected 2-fluoroinosine 23. While few previous studies of nitrosamine-DNA adducts have elaborated absolute stereochemistry (16,25,26), this has been an area of extensive research in the study of DNA adducts of polycyclic aromatic hydrocarbons (27)(28)(29). The results of those studies clearly demonstrate that the absolute stereochemistry of DNA adducts is critical in determining their mutagenic and carcinogenic effects.…”

Section: Discussionmentioning

confidence: 99%

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

Upadhyaya

McIntee

Villalta

et al. 2006

Chem. Res. Toxicol.

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N′-Nitrosonornicotine (NNN) is believed to play an important role as a cause of cancer in people who use tobacco products and is considered to be a human carcinogen. NNN requires metabolism to form DNA adducts, which are absolutely critical to its carcinogenic properties. Previous studies have identified cytochrome P450-catalyzed 2′-and 5′-hydroxylation of NNN as potential DNA adduct forming metabolic pathways. 5′-Hydroxylation is the more prevalent of these in monkeys and humans, and is known to generate mutagenic intermediates, but the DNA adducts formed by this pathway have never been characterized. In this study, we used 5′-acetoxyNNN as a stable precursor to 5′-hydroxyNNN, and investigated its esterase-catalyzed reactions with deoxyguanosine (dGuo) and DNA. Adducts resulting from carbocation and oxonium ion intermediates, produced by the spontaneous decomposition of 5′-hydroxyNNN, were identified. The carbocation pathway resulted in the formation of 2-[2-hydroxy-5-(3-pyridyl)pyrrolidin-1-yl]deoxyinosine (12) which was characterized by comparison to an independently synthesized standard. Treatment of 12 with NaBH 3 CN produced two diastereomers of 2-[2-(3-pyridyl)pyrrolidin-1-yl]deoxyinosine (14), and their absolute configurations at the 2-position were determined by comparison to synthetic standards. The oxonium ion pathway produced diastereomers of N 2 [5-(3-pyridyl)tetrahydrofuran-2-yl]dGuo (16), identified by comparison to synthetic standards. The absolute configuration at the 5-position was determined by establishing the stereochemistry of the enantiomers of 5-(3-pyridyl)-2-hydroxytetrahydrofuran at the 5-position, and allowing these to react individually with dGuo. Treatment of 16 with NaBH 3 CN produced N 2 [4-hydroxy-4-(3-pyridyl)but-1-yl]dGuo (18) which was also synthesized independently. Using liquid chromatography-electrospray ionization-tandem mass spectrometry with selected reaction monitoring, adducts 12 and 16 were identified as products of the reactions of 5′-acetoxyNNN with dGuo. Similarly, adducts 14 and 18 were identified as products of the reaction of 5′-acetoxyNNN with DNA followed by NaBH 3 CN treatment and enzymatic hydrolysis. These results provide the first structural characterization of DNA adducts that can be formed by 5′-hydroxylation of NNN.

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Section: Discussionmentioning

confidence: 99%

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

Upadhyaya

McIntee

Villalta

et al. 2006

Chem. Res. Toxicol.

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“…species that cause DNA damage (Szeliga and Dipple, 1998;Burczynski and Penning, 2000) resulting in G 1 cell cycle arrest (Vaziri and Faller, 1997). In contrast, the environmental pollutant TCDD, which is the most potent AhR agonist, induces CYP1A1 and modulates CYP1B1 expression in MCF-7 cells (Dohr et al, 1995), but is not directly genotoxic.…”

Section: Discussionmentioning

confidence: 99%

DNA damage and cell cycle arrest induced by 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells

et al. 2003

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“…Other reviews emphasize the chemistry of adduct formation and laboratory methodology Reddy, 2000;Szeliga and Dipple, 1998). Although most recent studies have employed only a few analytical approaches (i.e.…”

Section: Recent Reviewsmentioning

confidence: 99%

DNA adduct burden and tobacco carcinogenesis

Wiencke

2002

Oncogene

149

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DNA adducts associated with tobacco smoking could provide a marker of biologically effective dose of tobacco carcinogens and improve individual cancer risk prediction. A significant number of clinical and epidemiologic studies have reported associations of increased DNA adduct levels with the occurrence of the prevalent tobacco related cancers including cancer of the lung, head and neck, and bladder. The inducibility of DNA adducts following in vitro treatments using blood lymphocytes also appears to be a risk factor in the development of lung and head and neck cancer. Corroborative evidence pointing to the importance of DNA adducts in tobacco carcinogenesis include numerous studies showing associations of tobacco smoke exposure with the induction of DNA adducts in humans in vivo. Further effort is necessary, however, to more fully characterize the dose -response relationship between smoking and DNA adducts in exposed target and surrogate tissues. The relationship between gene polymorphisms thought to modify tobacco-related cancer risk and DNA adduct levels is complex. Results of some DNA adduct studies (both in vitro and in vivo) appear inconsistent with the epidemiologic findings. This is evident for polymorphisms involving both carcinogen metabolism (e.g. GSTP1) and DNA repair (e.g. XRCC1). Molecular studies of human tumors suggest associations of p53 mutation with DNA adducts and have revealed correlations of DNA adduct levels with somatic alterations (e.g. 3p21 LOH) that are thought to occur at the very earliest stages of tobacco carcinogenesis. More research is needed to assess the relationship between endogenous sources of DNA adducts and tobacco smoke exposure and the relative oncogenic effects of chemically stable versus unstable DNA adducts. Many potentially fruitful new avenues of cancer research are emerging that integrate DNA adduct analyses with assessments of smoking, genetics, diet and ambient air quality. These investigations aim to understand the multifactorial nature of interindividual variability in response to tobacco carcinogens. As these trends continue a variety of innovative study designs and approaches will become important in human populations.

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DNA Adduct Formation by Polycyclic Aromatic Hydrocarbon Dihydrodiol Epoxides

Cited by 204 publications

References 49 publications

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

DNA damage and cell cycle arrest induced by 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells

DNA adduct burden and tobacco carcinogenesis

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