Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents

Osada, Yoshio; Tsuchimoto, Masahiro; Fukushima, Hisashi; Takahashi, Katsushi; Kondô, Shirô; Hasegawa, Masaichi; Komoriya, Keiji

doi:10.1016/0014-2999(93)90201-r

Cited by 154 publications

(105 citation statements)

References 13 publications

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“…In reference to the vehicle control, M 1 dG metabolism was inhibited by allopurinol (7%) and stimulated by menadione (195%). Menadione and other quinones can be reduced by flavoproteins such as xanthine oxidase during the oxidation of reducing substrates (22), thereby stimulating oxidation (23,24). Thus, preliminary in vitro data implicate xanthine oxidase in the oxidation of M 1 dG in rat liver cytosol.…”

Section: Resultsmentioning

confidence: 94%

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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Section: Resultsmentioning

confidence: 94%

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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“…Rat xanthine oxidase was prepared from rat liver according to a previous report with minor modifications. 24) In brief, the liver was excised from a non-fasted 7-week-old male Wistar rat (Japan SLC, Inc., Hamamatsu, Japan), homogenized in 50 mM phosphate buffer (pH 7.4), and then centrifuged at 10,000 × g for 60 min at 4°C. The resulting supernatant was used as rat xanthine oxidase.…”

Section: Preparation Of Cfo Cfo (Kaneka Chrysflavonementioning

confidence: 99%

Administered chrysanthemum flower oil attenuates hyperuricemia: mechanism of action as revealed by DNA microarray analysis

Honda

Kawamoto

Tanaka

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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“…1B) is another recently developed inhibitor of XOR. When tested in rats and chimpanzees, its inhibition of uric acid production in vivo was stronger and lasted longer than that of allopurinol, without causing any noticeable side effects (21,22). The molecular structure of this inhibitor is quite dissimilar to that of substrates like xanthine or hypoxanthine, strongly suggesting that its mode of action will be different from that of allopurinol.…”

mentioning

confidence: 96%

An Extremely Potent Inhibitor of Xanthine Oxidoreductase

Okamoto

Eger

Nishino

et al. 2003

Journal of Biological Chemistry

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366

159

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TEI-6720 (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid) is an extremely potent inhibirespectively. Fluorescence-monitored titration experiments showed that TEI-6720 bound very tightly to both the active and the inactive desulfo-form of the enzyme. The dissociation constant determined for the desulfoform was 2 ؎ 0.03 ؋ 10 ؊9 M; for the active form, the corresponding number was too low to allow accurate measurements. The crystal structure of the active sulfoform of milk xanthine dehydrogenase complexed with TEI-6720 and determined at 2.8-Å resolution revealed the inhibitor molecule bound in a long, narrow channel leading to the molybdenum-pterin active site of the enzyme. It filled up most of the channel and the immediate environment of the cofactor, very effectively inhibiting the activity of the enzyme through the prevention of substrate binding. Although the inhibitor did not directly coordinate to the molybdenum ion, numerous hydrogen bonds as well as hydrophobic interactions with the protein matrix were observed, most of which are also used in substrate recognition.

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Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents

Cited by 154 publications

References 13 publications

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

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

Administered chrysanthemum flower oil attenuates hyperuricemia: mechanism of action as revealed by DNA microarray analysis

An Extremely Potent Inhibitor of Xanthine Oxidoreductase

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Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents

Cited by 154 publications

References 13 publications

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

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

Administered chrysanthemum flower oil attenuates hyperuricemia: mechanism of action as revealed by DNA microarray analysis

An Extremely Potent Inhibitor of Xanthine Oxidoreductase

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Product

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

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