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Cyclic adducts and intermediates induced by simple epoxides.

J J Solomon1

  • 1Nelson Institute of Environmental Medicine, New York University School of Medicine 10987, USA.

IARC Scientific Publications
|January 8, 2000
PubMed
Summary

Simple epoxides, industrial chemicals, are mutagenic and carcinogenic. They form DNA adducts that can rearrange into stable, potentially mutagenic forms, contributing to their biological activity.

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Area of Science:

  • Chemical carcinogenesis
  • Molecular toxicology
  • DNA adducts

Background:

  • Simple epoxides (e.g., ethylene oxide) are mutagenic and carcinogenic industrial chemicals.
  • These epoxides can also be formed metabolically from common industrial compounds like alkenes and vinyl monomers.
  • Epoxides are known to react with DNA, forming hydroxyalkyl adducts.

Purpose of the Study:

  • To elucidate the chemical mechanisms by which simple epoxides interact with DNA.
  • To understand the stability and mutagenicity of the resulting DNA adducts.
  • To investigate the role of adduct rearrangement in the biological activity of epoxides.

Main Methods:

  • Analysis of DNA adduct formation via SN2 mechanism.
  • Investigation of the chemical stability of hydroxyalkyl adducts at various DNA sites (N7-deoxyguanosine, N3-deoxyadenosine, N1-deoxyadenosine, N3-deoxycytidine).

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  • Characterization of adduct rearrangement pathways, including hydrolytic deamination and Dimroth rearrangement.

    • Main Results:

    • Simple epoxides form 2-hydroxy-2-alkyl adducts with DNA, predominantly at ring nitrogens.
    • Major adducts at N7-deoxyguanosine and N3-deoxyadenosine are unstable and depurinate, forming abasic sites.
    • Adducts at N1-deoxyadenosine and N3-deoxycytidine undergo rearrangements (e.g., deamination, Dimroth) to form stable, uncharged, potentially mutagenic adducts.

    Conclusions:

    • The chemical instability of initial epoxide-DNA adducts is a key factor in their mutagenicity.
    • Rearrangement pathways lead to stable, uncharged adducts that are likely responsible for the observed biological activity of simple epoxides.
    • Understanding these mechanisms is crucial for assessing the risks associated with exposure to simple epoxides.