Abstract
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.
Highlights
Produced DNA damage is a contributing factor to the progression of several genetic diseases, including cancer [1, 2]
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--D-erythropentofuranosyl)-pyrimido[1,2-␣]purine-10(3H)one (M1dG), is subject to enzymatic oxidation in vivo resulting in the formation of a major metabolite, 6-oxo-M1dG
Summary
All chemicals were obtained from commercial sources and used as received. Solvents were of HPLC grade purity or higher. Purified bovine xanthine oxidase was purchased from Calbiochem. Catheterized male Sprague-Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). HPLC-UV -RAM separations were performed on a Waters 2695 autosampler and binary pump with a Waters 2487 dual wave-
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