scholarly journals Chemical modification of DNA with muta-carcinogens. I. 3-Amino-1-methyl-5H-pyrido[4,3-b]indole and 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole: metabolic activation and structure of the DNA adducts.

1985 ◽  
Vol 62 ◽  
pp. 209-214 ◽  
Author(s):  
Y Hashimoto ◽  
K Shudo
Keyword(s):  
Chemical Modification ◽  
Dna Adducts ◽  
Metabolic Activation

Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A

2018 ◽  
Vol 154 ◽  
pp. 64-74 ◽  
Author(s):  
Alessia Stornetta ◽  
Kai-Cheng Kieren Deng ◽  
Sara Danielli ◽  
H.D. Sarath Liyanage ◽  
Shana J. Sturla ◽  
...  
Keyword(s):  
Dna Adducts ◽  
Nitrogen Mustard ◽  
Metabolic Activation ◽  
Nitro Aromatic

Characterization of highly polar bis-dihydrodiol epoxide—DNA adducts formed after metabolic activation of dibenz[a,h]anthracene

1993 ◽  
Vol 14 (5) ◽  
pp. 863-867 ◽  
Author(s):  
Jürgen Fuchs ◽  
Jiri Mlcoch ◽  
Karl-Ludwig Platt ◽  
Franz Oesch
Keyword(s):  
Dna Adducts ◽  
Metabolic Activation

Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine

2006 ◽  
Vol 231 (1) ◽  
pp. 138-145 ◽  
Author(s):  
Qingsu Xia ◽  
Ming W. Chou ◽  
John A. Edgar ◽  
Daniel R. Doerge ◽  
Peter P. Fu
Keyword(s):  
Dna Adducts ◽  
Pyrrolizidine Alkaloid ◽  
Metabolic Activation

scholarly journals Metabolic Activation and Carcinogenesis of Tobacco-Specific Nitrosamine N’-Nitrosonornicotine (NNN): A Density Function Theory and Molecular Docking Study

2019 ◽  
Vol 16 (2) ◽  
pp. 178 ◽  
Author(s):  
Tengjiao Fan ◽  
Guohui Sun ◽  
Lijiao Zhao ◽  
Xin Cui ◽  
Rugang Zhong
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Dft Calculations ◽  
Dna Adducts ◽  
Density Functional ◽  
Metabolic Activation ◽  
Docking Study ◽  
Tumor Formation ◽  
International Agency ◽  
Energy Barriers

N’-nitrosonornicotine (NNN) is one of the tobacco-specific nitrosamines (TSNAs) that exists widely in smoke and smokeless tobacco products. NNN can induce tumors in various laboratory animal models and has been identified by International Agency for Research on Cancer (IARC) as a human carcinogen. Metabolic activation of NNN is primarily initiated by cytochrome P450 enzymes (CYP450s) via 2′-hydroxylation or 5′-hydroxylation. Subsequently, the hydroxylating intermediates undergo spontaneous decomposition to generate diazohydroxides, which can be further converted to alkyldiazonium ions, followed by attacking DNA to form various DNA damages, such as pyridyloxobutyl (POB)-DNA adducts and pyridyl-N-pyrrolidinyl (py-py)-DNA adducts. If not repaired correctly, these lesions would lead to tumor formation. In the present study, we performed density functional theory (DFT) computations and molecular docking studies to understand the mechanism of metabolic activation and carcinogenesis of NNN. DFT calculations were performed to explore the 2′- or 5′- hydroxylation reaction of (R)-NNN and (S)-NNN. The results indicated that NNN catalyzed by the ferric porphyrin (Compound I, Cpd I) at the active center of CYP450 included two steps, hydrogen abstraction and rebound reactions. The free energy barriers of the 2′- and 5′-hydroxylation of NNN are 9.82/8.44 kcal/mol (R/S) and 7.99/9.19 kcal/mol (R/S), respectively, suggesting that the 2′-(S) and 5′-(R) pathways have a slight advantage. The free energy barriers of the decomposition occurred at the 2′-position and 5′-position of NNN are 18.04/18.02 kcal/mol (R/S) and 18.33/19.53 kcal/mol (R/S), respectively. Moreover, we calculated the alkylation reactions occurred at ten DNA base sites induced by the 2′-hydroxylation product of NNN, generating the free energy barriers ranging from 0.86 to 4.72 kcal/mol, which indicated that these reactions occurred easily. The docking study showed that (S)-NNN had better affinity with CYP450s than that of (R)-NNN, which was consistent with the experimental results. Overall, the combined results of the DFT calculations and the docking obtained in this study provide an insight into the understanding of the carcinogenesis of NNN and other TSNAs.

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