Endogenously occurring damage to DNA is a contributing factor to the onset of several genetic diseases, including cancer. Monitoring urinary levels of DNA adducts is one approach to assess genomic exposure to endogenous damage. However, metabolism and alternative routes of elimination have not been considered as factors that may limit the detection of DNA adducts in urine. We recently demonstrated that the peroxidation-derived deoxyguanosine adduct, 3-(2-deoxy-beta-D-erythropentofuranosyl)-pyrimido[1,2-alpha]purine-10(3H)-one (M1dG), is subject to enzymatic oxidation in vivo resulting in the formation of a major metabolite, 6-oxo-M1dG. Based on the administration of [14C]M1dG (22 microCi/kg) to Sprague-Dawley rats (n=4), we now report that 6-oxo-M1dG is the principal metabolite of M1dG in vivo representing 45% of the total administered dose. When [14C]6-oxo-M1dG was administered to Sprague-Dawley rats, 6-oxo-M1dG was recovered unchanged (>97% stability). These studies also revealed that M1dG and 6-oxo-M1dG are subject to biliary elimination. Additionally, both M1dG and 6-oxo-M1dG exhibited a long residence time following administration (>48 h), and the major species observed in urine at late collections was 6-oxo-M1dG.
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Base-Displaced Intercalated Structure of the 3-(2-Deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-]purine-6,10(3,5)-dione (6-oxo-MdG) Lesion in DNA.
Chem Res Toxicol
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Departments of Chemistry and Biochemistry, and the Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States.
The genotoxic 3-(2-deoxy-β-D-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one (MdG) DNA lesion arises from endogenous exposures to base propenals generated by oxidative damage and from exposures to malondialdehyde (MDA), produced by lipid peroxidation. Once formed, MdG may oxidize, , to 3-(2-deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-]purine-6,10(3,5)-dione (6-oxo-MdG). The latter blocks DNA replication and is a substrate for error-prone mutagenic bypass by the Y-family DNA polymerase hpol η.
View Article and Find Full Text PDFSynthesis of Nucleoside and Nucleotide Analogues by Cyclization of the Guanine Base with 1,1,3,3-Tetramethoxypropane.
Org Lett
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School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China.
3-(2-Deoxy-β-d-erythropentofuranosyl)pyrimido[1,2-]purin-10(3)-one (MdG) is an endogenous DNA adduct in bacterial and mammalian cells that could be explored as a biomarker for oxidative stress. Nonetheless, the lack of an efficient methodology for the preparation of MdG hampers the deep investigation of its biosynthesis and biorelevant processes. In this project, we aimed to address this issue by developing a highly efficient method to synthesize MdG and its analogues.
View Article and Find Full Text PDFMetabolism and elimination of the endogenous DNA adduct, 3-(2-deoxy-beta-D-erythropentofuranosyl)-pyrimido[1,2-alpha]purine-10(3H)-one, in the rat.
J Biol Chem
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A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Endogenously occurring damage to DNA is a contributing factor to the onset of several genetic diseases, including cancer. Monitoring urinary levels of DNA adducts is one approach to assess genomic exposure to endogenous damage. However, metabolism and alternative routes of elimination have not been considered as factors that may limit the detection of DNA adducts in urine.
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