Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts

Abstract

Non-invasive strategies for the analysis of endogenous DNA damage are of interest for the purpose of monitoring genomic exposure to biologically produced chemicals. We have focused our research on the biological processing of DNA adducts and how this may impact the observed products in biological matrixes. Preliminary research has revealed that pyrimidopurinone DNA adducts are subject to enzymatic oxidation in vitro and in vivo and that base adducts are better substrates for oxidation than the corresponding 2′-deoxynucleosides. We tested the possibility that structurally similar exocyclic base adducts may be good candidates for enzymatic oxidation in vitro. We investigated the in vitro oxidation of several endogenously occurring etheno adducts [1,N2-ε-guanine (1,N2-ε-Gua), N2,3-ε-Gua, heptanone-1,N2-ε-Gua, 1,N6-ε-adenine (1,N6-ε-Ade), and 3,N4-ε-cytosine (3,N4-ε-Cyt)] and their corresponding 2′-deoxynucleosides. Both 1,N2-ε-Gua and heptanone-1,N2-ε-Gua were substrates for enzymatic oxidation in rat liver cytosol; heteronuclear NMR experiments revealed that oxidation occurred on the imidazole ring of each substrate. In contrast, the partially or fully saturated pyrimidopurinone analogues [i.e., 5,6-dihydro-M1G and 1,N2-propanoguanine (PGua)] and their 2′-deoxynucleoside derivatives were not oxidized. The 2′-deoxynucleoside adducts, 1,N2-ε-dG and 1,N6-ε-dA, underwent glycolytic cleavage in rat liver cytosol. Together, these data suggest that multiple exocyclic adducts undergo oxidation and glycolytic cleavage in vitro in rat liver cytosol, in some instances in succession. These multiple pathways of biotransformation produce an array of products. Thus, the biotransformation of exocyclic adducts may lead to an additional class of biomarkers suitable for use in animal and human studies.

Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates

“…Both adducts have been studied as urinary biomarkers95–97,137–141 in their 2-deoxynucleoside forms. However, as recently observed by Marnett and coworkers, M 1 dG and substituted and unsubstituted etheno adducts are subject to metabolism, presumably in the liver 150–153. With regard to etheno adducts, 2-deoxynucleoside forms of G-derived etheno adducts are subject to deglycosylation followed by oxidation of 1, N 2 -ε-G to 2-oxo-1, N 2 -ε-G and of the corresponding substituted adduct, heptanone-1, N 2 -ε-G, to 2-oxoheptanone-1, N 2 -ε-G 153.…”

“…However, as recently observed by Marnett and coworkers, M 1 dG and substituted and unsubstituted etheno adducts are subject to metabolism, presumably in the liver 150–153. With regard to etheno adducts, 2-deoxynucleoside forms of G-derived etheno adducts are subject to deglycosylation followed by oxidation of 1, N 2 -ε-G to 2-oxo-1, N 2 -ε-G and of the corresponding substituted adduct, heptanone-1, N 2 -ε-G, to 2-oxoheptanone-1, N 2 -ε-G 153. With M 1 dG, metabolic and pharmacokinetic studies in rats revealed a biphasic elimination from plasma with M 1 dG found in the urine for more than 24 hr after dosing 150.…”

Palliative care benefits patients with lung cancer

“…Both adducts have been studied as urinary biomarkers95–97, 137–141 in their 2‐deoxynucleoside forms. However, as recently observed by Marnett and coworkers, M 1 dG and substituted and unsubstituted etheno adducts are subject to metabolism, presumably in the liver 150–153. With regard to etheno adducts, 2‐deoxynucleoside forms of G‐derived etheno adducts are subject to deglycosylation followed by oxidation of 1, N 2‐ε‐G to 2‐oxo‐1, N 2 ‐ε‐G and of the corresponding substituted adduct, heptanone‐1, N 2 ‐ε‐G, to 2‐oxoheptanone‐1, N 2 ‐ε‐G 153.…”

“…However, as recently observed by Marnett and coworkers, M 1 dG and substituted and unsubstituted etheno adducts are subject to metabolism, presumably in the liver 150–153. With regard to etheno adducts, 2‐deoxynucleoside forms of G‐derived etheno adducts are subject to deglycosylation followed by oxidation of 1, N 2‐ε‐G to 2‐oxo‐1, N 2 ‐ε‐G and of the corresponding substituted adduct, heptanone‐1, N 2 ‐ε‐G, to 2‐oxoheptanone‐1, N 2 ‐ε‐G 153. With M 1 dG, metabolic and pharmacokinetic studies in rats revealed a biphasic elimination from plasma with M 1 dG found in the urine for more than 24 hr after dosing 150.…”

Electrocatalytic activity of [Ru(bpy)3]2+ toward guanine oxidation upon incorporation of surfactants and SWCNTs

“…Many considerable efforts have been focused on the oxidation of DNA and its bases because of their important role in the process of mutagenesis and carcinogenesis as well as cancer therapeutics [1,2]. Guanine is the most easily oxidized bases in DNA and the electrochemical detection of DNA in biological samples is based on the oxidation of guanine [3][4][5].…”