Reaction of Malonaldehyde with Nucleic Acid. I. Formation of Fluorescent Pyrimido[1,2-<i>a</i>]purin-10(3<i>H</i>)-one Nucleosides

Seto, Hiroshi; Okuda, Taisuke; Takesue, Tomoyuki; Ikemura, Tadashi

doi:10.1246/bcsj.56.1799

Cited by 85 publications

(48 citation statements)

References 11 publications

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“…C, 14 C recovery in bile from bile-catheterized animals. The remaining 10% of the radioactivity was distributed among five distinct peaks in the radiochemical profiles, part of which (ϳ5%) was attributed to the [8][9][10][11][12][13][14] C]dG in the dosing solution. Thus, metabolites other than 6-oxo-M 1 dG collectively accounted for Ͻ6% of the total radioactivity.…”

Section: Resultsmentioning

confidence: 99%

“…(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). Iodoacrolein was freshly prepared from ethyl cis 3-iodoacrylate as described previously and dissolved in anhydrous N,N-dimethylformamide (22).…”

Section: Methodsmentioning

confidence: 99%

“…3-(2-Deoxy-␤-D-erythropentofuranosyl)-pyrimido[1,2-␣]purine-10(3H)-one (M 1 dG) 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)(6)(7)(8)(9)(10)(11). This adduct is mutagenic in bacteria and mammalian cells (12)(13)(14)(15) and is a substrate for nucleotide excision repair (13,16).…”

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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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“…It is derived from the lipid oxidation product, malondialdehyde, or the DNA oxidation product, base propenal (Scheme 1) (9)(10)(11). M 1 dG is miscoding when assayed by in vitro DNA replication and is mutagenic in bacterial and mammalian cells (12)(13)(14).…”

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confidence: 99%

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

Otteneder¹,

Knutson²,

Daniels³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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3-(2-Deoxy-␤-D-erythro-pentofuranosyl)pyrimido[1,2-␣]purin-10(3H)-one (M1dG) is a DNA adduct arising from the reaction of 2-deoxyguanosine with the lipid peroxidation product, malondialdehyde, or the DNA peroxidation product, base propenal. M 1dG is mutagenic in bacteria and mammalian cells and is present in the genomic DNA of healthy human beings. It is also detectable, albeit at low levels, in the urine of healthy individuals, which may make it a useful biomarker of DNA damage linked to oxidative stress. We investigated the possibility that the low urinary levels of M 1dG reflect metabolic conversion to derivatives. M 1dG was rapidly removed from plasma (t1/2 ‫؍‬ 10 min) after i.v. administration to rats. A single urinary metabolite was detected that was identified as 6-oxo-M 1dG by MS, NMR spectroscopy, and independent chemical synthesis. 6-Oxo-M1dG was generated in vitro by incubation of M 1dG with rat liver cytosols, and studies with inhibitors suggested that xanthine oxidase and aldehyde oxidase are involved in the oxidative metabolism. M1dG also was metabolized by three separate human liver cytosol preparations, indicating 6-oxo-M1dG is a likely metabolite in humans. This represents a report of the oxidative metabolism of an endogenous DNA adduct and raises the possibility that other endogenous DNA adducts are metabolized by oxidative pathways. 6-Oxo-M1dG may be a useful biomarker of endogenous DNA damage associated with inflammation, oxidative stress, and certain types of cancer chemotherapy.excretion ͉ inflammation ͉ DNA damage ͉ oxidation ͉ metabolite D NA damage from endogenous sources is believed to contribute significantly to human genetic diseases, including cancer (1, 2). A major cause of endogenous DNA damage is oxidation (3, 4). Agents such as hydroxyl radical or peroxynitrous acid oxidize nucleic acid bases or the deoxyribose backbone to form miscoding lesions or induce strand breaks (5). In addition, oxidation of other cellular constituents (i.e., lipid, protein) generates reactive derivatives that form adducts with nucleic acid bases (1). In the absence of repair, this panoply of damage results in mutations, triggers signaling to arrest cell division, or induces apoptosis.3-(2-Deoxy-␤-D-er ythro-pentofuranosyl)pyrimido[1,2-␣]purin-10(3H)-one (M 1 dG) is an adduct found at varying levels in genomic DNA of rodents and humans (6-8). It is derived from the lipid oxidation product, malondialdehyde, or the DNA oxidation product, base propenal (Scheme 1) (9-11). M 1 dG is miscoding when assayed by in vitro DNA replication and is mutagenic in bacterial and mammalian cells (12)(13)(14). It induces base pair substitutions (M 1 dG3T and M 1 dG3A) and frameshift mutations in reiterated sequences (e.g., CG n ) when shuttle vectors containing a site-specific lesion are replicated in COS-7 cells (14). Genetic and biochemical experiments indicate that M 1 dG is removed by nucleotide excision repair in both bacterial and mammalian cells (13-15).As a prerequisite for preclinical, clinical, and populationbased ...

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“…In aqueous solution, MDA exists as β-hydroxyacrolein. It reacts with DNA as a bis-electrophile to form M 1 dG (3)(4)(5)(6)(7). Alternatively, the M 1 dG adduct arises as a consequence of oxidative damage to DNA, resulting in the formation of base propenals that subsequently transfer their oxopropenyl group to dG (8) (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Bulge Migration of the Malondialdehdye OPdG DNA Adduct When Placed Opposite a Two-Base Deletion in the (CpG)₃ Frameshift Hotspot of the Salmonella typhimurium hisD3052 Gene

Wang

Schnetz-Boutaud

Saleh

et al. 2007

Chem. Res. Toxicol.

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The OPdG adduct N 2 -(3-oxo-1-propenyl)dG, formed in DNA exposed to malondialdehyde, was introduced into 5′-d(ATCGCXCGGCATG)-3′•5′-d(CATGCCGCGAT)-3′ at pH 7 (X = OPdG). The OPdG adduct is the base-catalyzed rearrangement product of the M 1 dG adduct, 3-(β-D-ribofuranosyl) pyrimido[1,2-a]purin-10(3H)-one. This duplex, named the OPdG-2BD oligodeoxynucleotide, was derived from a frameshift hotspot of the Salmonella typhimuium hisD3052 gene and contained a twobase deletion in the complementary strand. NMR spectroscopy revealed that the OPdG-2BD oligodeoxynucleotide underwent rapid bulge migration. This hindered its conversion to the M 1 dG-2BD duplex, in which the bulge was localized and consisted of the M 1 dG adduct and the 3′-neighbor dC [Schnetz-Boutaud, N. C., Saleh, S., Marnett, L. J., and Stone, M. P. (2001) Biochemistry 40, 15638−15649]. The spectroscopic data suggested that bulge migration transiently positioned OPdG opposite dC in the complementary strand, hindering formation of the M 1 dG-2BD duplex, or alternatively, reverting rapidly formed intermediates in the OPdG to M 1 dG reaction pathway when dC was placed opposite from OPdG. The approach of initially formed M 1 dG-2BD or OPdG-2BD duplexes to an equilibrium mixture of the M 1 dG-2BD and OPdG-2BD duplexes was monitored as a function of time, using NMR spectroscopy. Both samples attained equilibrium in ∼140 days at pH 7 and 25 °C. (Tables S1 and S2, respectively) and chemical shifts of exchangeable protons for the OPdG-and M 1 dG-2BD duplexes (Tables S3 and S4, respectively). This material is available free of charge via the Internet at

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Reaction of Malonaldehyde with Nucleic Acid. I. Formation of Fluorescent Pyrimido[1,2-a]purin-10(3H)-one Nucleosides

Cited by 85 publications

References 11 publications

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

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

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

Bulge Migration of the Malondialdehdye OPdG DNA Adduct When Placed Opposite a Two-Base Deletion in the (CpG)₃ Frameshift Hotspot of the Salmonella typhimurium hisD3052 Gene

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Reaction of Malonaldehyde with Nucleic Acid. I. Formation of Fluorescent Pyrimido[1,2-a]purin-10(3H)-one Nucleosides

Cited by 85 publications

References 11 publications

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

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

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M 1 dG

Bulge Migration of the Malondialdehdye OPdG DNA Adduct When Placed Opposite a Two-Base Deletion in the (CpG)3 Frameshift Hotspot of the Salmonella typhimurium hisD3052 Gene

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In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

Bulge Migration of the Malondialdehdye OPdG DNA Adduct When Placed Opposite a Two-Base Deletion in the (CpG)₃ Frameshift Hotspot of the Salmonella typhimurium hisD3052 Gene