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Updated: May 30, 2025

A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s
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Insight into the molecular initiating event of mutagenic N-nitrosamines: a computational study on DNA alkylation by

Shiyang Cheng1,2, Houjun Qiu1, Wen Ding1

  • 1School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou, China.

Environmental Toxicology and Chemistry
|January 30, 2025
PubMed

Insights

N-Nitrosamines are potent mutagens. Computational chemistry reveals how their metabolic products, diazonium ions, alkylate DNA, linking molecular initiating events to carcinogenicity and providing a mechanistic bridge to toxicity.

Area of Science:

  • Environmental Chemistry
  • Computational Chemistry
  • Toxicology

Background:

  • N-Nitrosamines are widespread environmental compounds with known mutagenic and carcinogenic properties.
  • Metabolic activation of N-nitrosamines yields diazonium ions, initiating DNA alkylation as a key step in toxicity.
  • The precise DNA base alkylation sites (regiochemistry) by these diazonium ions remain a subject of scientific debate.

Purpose of the Study:

  • To investigate the regiochemistry of DNA base alkylation by diverse diazonium ions using computational methods.
  • To explore the relationship between the chemical properties of alkylating agents and their mutagenic potential.
  • To establish a computational model linking molecular initiating events (MIE) to carcinogenic potency.

Main Methods:

  • Density functional theory (DFT) calculations were employed to simulate the SN2 alkylation of guanine (Gua) by 14 different diazonium ions.
  • Analysis of transition states to understand the shift in alkylation sites (GuaN7 vs. GuaO6).
  • Application of Hard and Soft Acids and Bases (HSAB) theory to quantify MIE selectivity and model relationships between nucleophilicity, hydrophobicity, and carcinogenic potency.

Main Results:

  • The study demonstrated a shift in alkylation from guanine N7 to O6 with increasing complexity of the alkylating diazonium ions.
  • A greater SN1 character was observed in SN2 transition states for more complex alkylating agents, suggesting a reclassification of "high/low oxyphilic" agents.
  • Quantitative relationships were established between the nucleophilic index (ω-), hydrophobicity (log P) of diazonium ions, and their carcinogenic potency.

Conclusions:

  • Computational chemistry provides a mechanistic link between molecular initiating events (DNA alkylation) and the target toxicity of N-nitrosamine-derived diazonium ions.
  • The complexity and electronic properties of alkylating agents significantly influence DNA alkylation regiochemistry and mutagenic potential.
  • This research offers a framework for predicting carcinogenic potency based on the chemical characteristics of diazonium ions.
Keywords:
N-nitrosaminesDNA alkylationdensity functional theory calculationsdiazonium ionsmolecular initiating event

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