Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-Nitropyrene is an environmental mutagen and carcinogen which undergoes both oxidative and reductive metabolism. We have previously shown that nitroreduction to N-hydroxy-1-aminopyrene leads to the formation of arylamine--DNA adducts. In the present study, we have investigated the oxidative metabolism of 1-nitropyrene and the subsequent binding of ring-oxidized metabolites to DNA. In vitro incubations were conducted using hepatic microsomes from uninduced rats or from rats pretreated with phenobarbital, Aroclor 1254, 3-methylcholanthrene, or 3-methylcholanthrene and trans-stilbene oxide. H.p.l.c. analysis of the incubation mixtures indicated the presence of the previously reported metabolites, 1-aminopyrene, 3-, 6-, and 8-hydroxy-1-nitropyrene, and 1-nitropyrene trans-4,5-dihydrodiol. In addition, 1-nitropyrene 4,5-oxide, 1-nitropyrene 9,10-oxide, 1-nitropyrene trans-9,10-dihydrodiol and 1-pyrenol were identified. The formation of both K-region dihydrodiols could be increased by trans-stilbene oxide induction of microsomal epoxide hydrase. Formation of the K-region epoxides was greatest using phenobarbital- and Aroclor-induced microsomes and increased with increasing oxygen tension, while 1-pyrenol formation was highest in 3-methylcholanthrene-induced microsomal incubations and was not affected by the oxygen tension. When calf thymus DNA was added to the microsomal incubations, similar levels of DNA-binding occurred in incubations conducted under oxygen, air, argon or anaerobic conditions. H.p.l.c. analysis of the enzymatically hydrolyzed DNA indicated the presence of multiple DNA adducts with the major product coeluting with N-(deoxyguanosin-8-yl)-1-aminopyrene. The K-region oxides bound directly to DNA to give adducts similar to the minor products detected in the microsomal incubations. Incubation of the K-region oxides with the nitroreductase, xanthine oxidase, increased the DNA-binding and resulted in an additional adduct which coeluted with N-(deoxyguanosin-8-yl)-1-amino pyrene. 3-Hydroxy-1-nitropyrene bound extensively to DNA upon nitroreduction by rat liver cytosol or xanthine oxidase, while 6- and 8-hydroxy-1-nitropyrene bound only slightly. None of these oxidized metabolites was activated to DNA-binding species by cytosolic nitroreduction followed by AcCoA-dependent acetylation. The fact that oxidized metabolites of 1-nitropyrene are reduced to DNA-binding derivatives more easily than 1-nitropyrene itself may be important in vivo where 1-nitropyrene has been shown to be readily oxidized.
Carcinogenesis 1986 Jul
PMID:Oxidative microsomal metabolism of 1-nitropyrene and DNA-binding of oxidized metabolites following nitroreduction. 375 82

[3H]1-Nitropyrene was administered at a dose of 25 mg/kg by i.p. injection to female Wistar rats. Animals were killed 24 h later and DNA was isolated from kidney, liver and mammary gland, enzymically hydrolysed and analysed by reverse-phase h.p.l.c. A major adduct peak was detected in DNA from each of the three organs. Enzymic hydrolysates of DNA, which had been reacted in vitro with 1-nitropyrene in the presence of xanthine oxidase, were similarly analysed by h.p.l.c. One major adduct peak was obtained which had the same retention time as the in vivo product. Confirmatory evidence that the in vivo adduct and the in vitro adduct were structurally similar was obtained from the determination of the pH-dependent solvent partitioning profiles. Further, treatment of the in vivo adduct from liver, kidney or mammary gland DNA hydrolysates and the in vitro adduct with sodium hydroxide resulted in the formation of a more polar product which eluted earlier on h.p.l.c. This behaviour is consistent with scission of the imidazole ring of a deoxyguanosine adduct. The major DNA adduct formed in vitro following xanthine oxidase reduction of 1-nitropyrene has previously been identified by others as N-(deoxyguanosin-8-yl)-1-aminopyrene. The present data suggest that the in vivo 1-nitropyrene-DNA adduct has the same structure.
Carcinogenesis 1985 Apr
PMID:Evidence for N-(deoxyguanosin-8-yl)-1-aminopyrene as a major DNA adduct in female rats treated with 1-nitropyrene. 383 6

In a study of the relation between chronic inflammation and carcinogenesis, C3H mouse fibroblasts of the 10T 1/2 clone 8 line (10T 1/2 cells) were exposed to human neutrophils stimulated to synthesize reactive oxygen intermediates or to a cell-free enzymatic system generating superoxide (xanthine oxidase plus hypoxanthine). After exposure, the 10T 1/2 cells were either placed in tissue culture or immediately injected into athymic nude mice. Both malignant and benign tumors developed in the mice injected with treated cells, but not in those injected with control cells; in one instance cells grown from one of the benign tumors subsequently developed a malignant phenotype. Malignant transformation was also observed in treated cells in the experiments in vitro.
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PMID:Phagocytes as carcinogens: malignant transformation produced by human neutrophils. 397 11

The oxidation of NH3 to NO3- by rat liver in vitro is described. A xanthine-xanthine oxidase reaction also oxidized NH3 to NO3- when H2O2 was added. An in vivo inhibitor of superoxide dismutase enhanced the in vitro liver conversion of NH3 to NO3-. Thus, intracellular oxidation by activated oxygen likely represents the source of endogenously formed NO3- in mammals.
Carcinogenesis 1984 Sep
PMID:Activated oxygen and mammalian nitrate biosynthesis. 608 4

There is much evidence from in vivo and in vitro carcinogenesis studies that active oxygen species play a role in tumor promotion. We tested directly whether superoxide produced extracellularly by xanthine-xanthine oxidase (X-XO) has the capacity to promote initiated mouse embryo C3H/10T1/2 fibroblasts. Cell cultures initiated with either 137Cs gamma-rays or benzo[a]pyrene diol epoxide I were found to transform 3-30 times more effectively when subsequently treated daily for 3 weeks with nontoxic doses of X-XO. Scavengers of active oxygen radicals such as superoxide dismutase or superoxide dismutase in combination with catalase reduced the frequency of appearance of transformed foci by 3-25 times when compared to cultures receiving X-XO alone. These results show that active oxygen species such as superoxide and H2O2 can act in a promotional manner that mimics the effects of the mouse skin promoter phorbol 12-myristate 13-acetate in this system. X-XO also acted as a weak complete carcinogen.
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PMID:Active oxygen acts as a promoter of transformation in mouse embryo C3H/10T1/2/C18 fibroblasts. 642 26

Antioxidant and antipromotional effects of the soybean isoflavone genistein have been studied in HL-60 cells and the mouse skin tumorigenesis model. Effects of structure-related flavone/isoflavones on hydrogen peroxide (H2O2) production by 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated HL-60 cells and superoxide anion (O2-) generation by xanthine/xanthine oxidase were compared. Of tested isoflavones, genistein is the most potent inhibitor among TPA-induced H2O2 formation by (dimethyl sulfoxide) DMSO-differentiated HL-60 cells, daidzein is second, and apigenin and biochanin A show little effect. In contrast, genistein, apigenin, and prunectin are equally potent in inhibiting O2- generation by xanthine/xanthine oxidase, with daidzein showing a moderate inhibitory effect and biochanin A exhibiting no effect. These results suggest that the antioxidant properties of isoflavones are structurally related and the hydroxy group at Position 4' is crucial in both systems. Dietary administration of 250 ppm genistein for 30 days significantly enhances the activities of antioxidant enzymes in the skin and small intestine of mice. Further studies show that genistein significantly inhibits TPA-induced proto-oncogene expression (c-fos) in mouse skin in a dose-dependent manner. In a two-stage skin carcinogenesis study, low levels of genistein (1 and 5 mumol) significantly prolong tumor latency and decrease tumor multiplicity by approximately 50%. We conclude that genistein's antioxidant properties and antiproliferative effects may be responsible for its anticarcinogenic effect. Its high content in soybeans and relatively high bioavailability favor genistein as a promising candidate for the prevention of human cancers.
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PMID:Antioxidant and antipromotional effects of the soybean isoflavone genistein. 789 86

Treatment of NIH3T3 cells with the tumor promoter phorbol-12-myristate-13-acetate (PMA) results within 30 min in a 1.8-fold elevation of xanthine oxidase (XO) activity, an enzyme capable of generating reactive oxygen species such as superoxide and hydrogen peroxide. Simultaneous administration of 2 and 10 microM curcumin with 100 ng/ml PMA inhibits PMA-induced increases in XO activity measured 30 min later by 22.7% and 36.5%, respectively. The PMA-induced conversion of xanthine dehydrogenase (XD) to XO is reduced by curcumin to the basal level noted in untreated cells. Activity of XO is remarkably inhibited by curcumin in vitro, but not by its structurally related compounds caffeic acid, chlorogenic acid and ferulic acid. Based on these findings, induction of XO activity is deemed to be one of the major causative elements in PMA-mediated tumor promotion, and the major inhibitory mechanism of curcumin on PMA-induced increases in XD/XO enzyme activities is through direct inactivation at the protein level.
Carcinogenesis 1994 Aug
PMID:Inhibitory effect of curcumin on xanthine dehydrogenase/oxidase induced by phorbol-12-myristate-13-acetate in NIH3T3 cells. 805 54

3-Nitrobenzo[a]pyrene (3-nitro-B[a]P) is a potent bacterial mutagen as a result of nitroreduction. Reaction of N-hydroxy-3-amino-B[a]P, prepared in situ from reduction of 3-nitro-B[a]P with calf thymus DNA, was studied. After enzymatic digestion of the DNA, the resulting modified nucleosides were analyzed by thermospray HPLC-MS and high-resolution proton NMR spectroscopy. The major adduct was identified as 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P. The same adduct was obtained from incubation of DNA with 3-nitro-B[a]P in the presence of the mammalian nitroreductase xanthine oxidase, and hypoxanthine. These data indicate that a mammalian nitroreductase can metabolize 3-nitro-B[a]P to an activated derivative that reacts with DNA to give a novel adduct distant from the site of N-hydroxylation.
Carcinogenesis 1993 May
PMID:Formation of the adduct 6-(deoxyguanosin-N2-yl)-3-amino-benzo[a]pyrene from the mutagenic environmental contaminant 3-nitrobenzo[a]pyrene. 816 85

DNA single-strand breaks (SSBs) and their disappearance during repair incubation were determined by alkaline filter elution in freshly isolated human peripheral blood lymphocytes (PBLs) after in vitro treatment with either the oxygen radical-generating system of xanthine oxidase (XOD) plus hypoxanthine (HYP) or the alkylating agent N-ethyl-N'-nitrosourea (ENU). The elution curves obtained with DNA from PBLs treated with XOD/HYP were markedly nonlinear, possibly as a result of a nonrandom induction of SSBs along the DNA strands. The disappearance of XOD/HYP-induced SSBs during the initial repair period was quite slow; only 20 +/- 7% (n = 6) of the induced SSBs had disappeared after a 2 1/2 h repair incubation. However, by 24 h the elution curves obtained with DNA from treated PBLs were indistinguishable from those obtained with DNA from nontreated control cells, indicating complete repair. Treatment of PBLs with ENU resulted in linear elution curves. Approximately 50% of the total amount of ENU-induced SSBs had disappeared within 1 h in PBLs from most donors; the additional SSBs were found to be persistent (Beorrigter, M.E.T.I., Mullaart, E., Berends, F., and Vijg, J. (1991) Induction and disappearance of DNA strand breaks and/or alkali-labile sites in human lymphocytes exposed to N-ethyl-N'-nitrosoureas. Carcinogenesis, 12, 77-82). Preincubation of PBLs with 5 mM L-carnitine, a trans-mitochondrial carrier of acetyl and long-chain acyl groups, or 5 mM acetyl-L-Carnitine, resulted in a more rapid disappearance of XOD/HYP-induced SSBs (48 +/- 23% and 48 +/- 30% respectively). Preincubation of PBLs with different doses of L-carnitine, before exposure to 0.5 mM ENU, increased SSB disappearance dependent on the dose and donor PBLs. In conclusion, these studies suggest that treatment with L-carnitine accelerates the disappearance of SSBs induced by oxygen radicals and alkylating agents.
Carcinogenesis 1993 Oct
PMID:The effect of L-carnitine and acetyl-L-carnitine on the disappearance of DNA single-strand breaks in human peripheral blood lymphocytes. 822 66

When irradiated at 360 nm, furocoumarins with a hydroperoxide group in a side chain efficiently give rise to a type of DNA damage that can best be explained by a photo-induced generation of hydroxyl radicals from the excited photosensitizers. The observed DNA damage profiles, i.e. the ratios of single-strand breaks, sites of base loss (AP sites) and base modifications sensitive to formamidopyrimidine--DNA glycosylase (FPG protein) and endonuclease III, are similar to the DNA damage profile produced by hydroxyl radicals generated by ionizing radiation or by xanthine and xanthine oxidase in the presence of Fe(III)--EDTA. No such damage is observed with the corresponding furocoumarin alcohols or in the absence of near-UV radiation. The damage caused by the photo-excited hydroperoxides is not influenced by superoxide dismutase (SOD) or catalase or by D2O as solvent. The presence of t-butanol, however, reduces both the formation of single-strand breaks and of base modifications sensitive to FPG protein. The cytotoxicity caused by one of the hydroperoxides in L5178Y mouse lymphoma cells is found to be dependent on the near-UV irradiation and to be much higher than that of the corresponding alcohol. Therefore the new type of photo-induced damage occurs inside cells. Intercalating photosensitizers with an attached hydroperoxide group might represent a novel and versatile class of DNA damaging agents, e.g. for phototherapy.
Carcinogenesis 1993 Nov
PMID:DNA damage induced by furocoumarin hydroperoxides plus UV (360 nm). 824 54


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