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Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling
Published on: March 20, 2018
Alkylating potential of α,β-unsaturated compounds
José A Manso1, Isaac F Céspedes Camacho, Emilio Calle
1Departamento de Química Física, Universidad de Salamanca, Salamanca, Spain.
Organic & Biomolecular Chemistry
|July 21, 2011
Summary
DNA alkylating agents like acrylonitrile, acrylamide, and acrylic acid react differently with guanosine. Reactivity correlates with adduct formation and mutagenicity, with acrolein showing unique behavior under cellular conditions.
Area of Science:
- Chemical kinetics
- DNA damage and repair
- Toxicology
Background:
- Nucleoside guanosine (Guo) can be alkylated by α,β-unsaturated compounds (α,β-UC).
- These α,β-UCs, including acrylonitrile (AN), acrylamide (AM), acrylic acid (AA), and acrolein (AC), are potential DNA alkylating agents.
- Understanding their reaction mechanisms and kinetics is crucial for assessing genotoxicity.
Purpose of the Study:
- To kinetically investigate the alkylation of guanosine by AN, AM, AA, and AC.
- To compare the alkylating potential and reaction mechanisms of these α,β-UCs.
- To correlate chemical reactivity with biomarker adduct formation and mutagenicity.
Main Methods:
- Kinetic analysis of guanosine alkylation reactions.
- Determination of rate constants and equilibrium constants.
- Investigation of reaction pH dependence.
Main Results:
- Acrolein (AC) exhibits a distinct Guo alkylation mechanism compared to AN, AM, and AA.
- The alkylating potential follows the order: AN > AM > AA.
- Reactivity correlates with biomarker adduct formation and mutagenicity.
- AN and AM alkylation proceed via Michael addition; AN is reversible, AM is irreversible.
- AC alkylates guanosine under cellular pH conditions, unlike AN, AM, and AA.
- The α-OH-Guo adduct formation is 1.5-fold faster than γ-OH-Guo.
Conclusions:
- The chemical reactivity of α,β-UCs correlates with their ability to form DNA adducts and induce mutagenicity.
- The distinct reactivity and pH-dependent behavior of AC suggest unique genotoxic risks.
- The reversibility of AN-Guo adduct formation may allow for repair, while AM adducts are persistent.
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