Oxidation and glycolytic cleavage of etheno and propano DNA base adducts.
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,N(2)-epsilon-guanine (1,N(2)-epsilon-Gua), N(2),3-epsilon-Gua, heptanone-1,N(2)-epsilon-Gua, 1,N(6)-epsilon-adenine (1,N(6)-epsilon-Ade), and 3,N(4)-epsilon-cytosine (3,N(4)-epsilon-Cyt)] and their corresponding 2'-deoxynucleosides. Both 1,N(2)-epsilon-Gua and heptanone-1,N(2)-epsilon-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-M(1)G and 1,N(2)-propanoguanine (PGua)] and their 2'-deoxynucleoside derivatives were not oxidized. The 2'-deoxynucleoside adducts, 1,N(2)-epsilon-dG and 1,N(6)-epsilon-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.
Knutson
Charles G
CG
A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Rubinson
Emily H
EH
Akingbade
Dapo
D
Anderson
Carolyn S
CS
Stec
Donald F
DF
Petrova
Katya V
KV
Kozekov
Ivan D
ID
Guengerich
F Peter
FP
Rizzo
Carmelo J
CJ
Marnett
Lawrence J
LJ
D000818:Animals; D002417:Cattle; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism*; D004260:DNA Repair; D006019:Glycolysis / Q000502:physiology*; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D011684:Purine Nucleosides / Q000737:chemistry* / Q000378:metabolism*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000378:metabolism; D051381:Rats
C491625:3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido(1,2-alpha)purin-10(3H)-one; C509413:3-(2-deoxypentofuranosyl)furo(2,3-d)pyrimidin-2(3H)-one; D018736:DNA Adducts; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides; C494608:cyclic 1,N(2)-propanoguanine; D006147:Guanine