“One-Pot” Syntheses of Malondialdehyde Adducts of Nucleosides

Székely, József I.; Wang, Hao; Peplowski, Katherine M.; Knutson, Charles G.; Marnett, Lawrence J.; Rizzo, Carmelo J.

doi:10.1080/15257770701795797

Cited by 20 publications

(21 citation statements)

References 17 publications

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“…[ 15 N 5 ]-6-oxo-M 1 dG was synthesized as described previously by substituting [ 15 N 5 ]-dG (Cambridge Isotope Laboratories, Andover, MA, USA) for dG ( 15 ). Similarly, [ 13 C, 15 N 2 ]-M 1 dG was synthesized as described previously by substituting [ 13 C, 15 N 2 ]-dG (Cambridge Isotope Laboratories, Andover, MA, USA) for dG ( 27 ).…”

Section: Methodsmentioning

confidence: 99%

Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA

Wauchope

Mitchener

Beavers

et al. 2018

Nucleic Acids Research

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Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50–100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/−) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.

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Section: Methodsmentioning

confidence: 99%

Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA

Wauchope

Mitchener

Beavers

et al. 2018

Nucleic Acids Research

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“…Section 1734 solely to indicate this fact. (21). Briefly, [8][9][10][11][12][13][14] C]2Ј-deoxyguanosine ( 14 C-dG) was obtained from Sigma (0.2 mCi, 55 mCi/mmol) as a solution in ethanol/ water (1:1).…”

Section: Methodsmentioning

confidence: 99%

Metabolism and Elimination of the Endogenous DNA Adduct, 3-(2-Deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-α]purine-10(3H)-one, in the Rat

Knutson¹,

Wang²,

Rizzo³

et al. 2007

Journal of Biological Chemistry

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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-␤-D-erythropentofuranosyl)-pyrimido[1,2-␣]purine-10(3H)-one (M 1 dG), is subject to enzymatic oxidation in vivo resulting in the formation of a major metabolite, 6-oxo-M 1 dG. Based on the administration of [ 14 C]M 1 dG (22 Ci/kg) to Sprague-Dawley rats (n ‫؍‬ 4), we now report that 6-oxo-M 1 dG is the principal metabolite of M 1 dG in vivo representing 45% of the total administered dose. When [ 14 C]6-oxo-M 1 dG was administered to Sprague-Dawley rats, 6-oxo-M 1 dG was recovered unchanged (>97% stability). These studies also revealed that M 1 dG and 6-oxo-M 1 dG are subject to biliary elimination. Additionally, both M 1 dG and 6-oxo-M 1 dG exhibited a long residence time following administration (>48 h), and the major species observed in urine at late collections was 6-oxo-M 1 dG.Endogenously produced DNA damage is a contributing factor to the progression of several genetic diseases, including cancer (1, 2). Furthermore, there is a strong association between chronic inflammation and cancer risk (3). Assessing exposure to endogenously produced electrophiles and oxidants may have an impact in risk assessment (4). Monitoring the levels of DNA adducts in urine is a common approach used to assess exposure to genomic damaging agents. However, factors that may limit the detection of DNA adducts in urine (metabolism, routes of elimination, etc.) have not previously been investigated.3 is an endogenous pyrimidopurinone adduct formed by reacting deoxyguanosine with malondialdehyde, a product of enzymatic and nonenzymatic lipid peroxidation reactions, or base propenal, a DNA peroxidation product (5-11). This adduct is mutagenic in bacteria and mammalian cells (12-15) and is a substrate for nucleotide excision repair (13,16). It is also one of the first endogenously occurring DNA damage products to be detected in DNA of healthy humans (17). Prior attempts to quantify the levels of M 1 dG in human urine demonstrated an excretion rate of 12 fmol/kg/24 h (18). The rate of M 1 dG elimination in rats could not be determined, because the levels were below the limit of detection for the analytical method (19). The low rate of elimination in human populations and the absence of observed material in the urine of rats led us to hypothesize that factors such as metabolism (oxidation, conjugation, etc.) or alternative routes of elimination may limit the appearance of M 1 dG in urine.We recently demonstrated that M 1 dG is subject to oxidative metabolism in the rat to a principal metabolite, 6-oxo-M 1 dG (20). However, the total recovery and extent of metabolism in these studies...

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“…The major product ion was at m/z 79 which can be explained by a six‐membered ring and is expected to be the most stable of the product ions. The two larger product ions have been identified by Szekely et al during the analysis of the corresponding nucleoside, M 1 dG, using multi‐stage MS/MS analysis. Protonated M 1 dG has an m/z of 304 and neutral loss of the deoxyribose unit (116 Da) occurred to give the protonated ion of M 1 G ( m/z 188) which is the starting point of our analyses.…”

Section: Resultsmentioning

confidence: 99%

Quantitative analysis of malondialdehyde‐guanine adducts in genomic DNA samples by liquid chromatography/tandem mass spectrometry

Yates

Dempster

Murphy

et al. 2017

Rapid Comm Mass Spectrometry

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A fast reliable sample preparation method was used to release adducts in the base form rather than the nucleoside. The methods were optimised to selectively analyse the adducts in the presence of other DNA bases without the need for further sample clean-up. Analysis of genomic DNA gave results consistent with previous work and was applied to new samples. Thus, the method is suitable for the analysis of M (d)G adducts in biological samples. Copyright © 2017 John Wiley & Sons, Ltd.

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“One-Pot” Syntheses of Malondialdehyde Adducts of Nucleosides

Cited by 20 publications

References 17 publications

Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA

Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA

Metabolism and Elimination of the Endogenous DNA Adduct, 3-(2-Deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-α]purine-10(3H)-one, in the Rat

Quantitative analysis of malondialdehyde‐guanine adducts in genomic DNA samples by liquid chromatography/tandem mass spectrometry

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