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

1. The mutagenicity of 1-nitropyrene metabolites in Chinese hamster ovary (CHO) cells, in the absence of rat liver S9, decreased in the order 6-hydroxy-1-nitropyrene > 1-nitropyrene 9,10-oxide > 1-nitropyrene 4,5-oxide approximately 3-hydroxy-1-nitropyrene approximately 8-hydroxy-1-nitropyrene > 1-nitropyrene. The order of mutagenicity with rat liver S9 was 1-nitropyrene 4,5-oxide approximately 6-hydroxy-1-nitropyrene approximately 1-nitropyrene 9,10-oxide > 3-hydroxy-1-nitropyrene approximately 1-nitropyrene > 8-hydroxy-1-nitropyrene. 2. 1-Nitropyrene 4,5-oxide reacted with calf thymus DNA to give one or several closely related adducts. The same adducts were detected in CHO cells incubated with 1-nitropyrene 4,5-oxide. Inclusion of a nitroreductase, xanthine oxidase, in the incubations with calf thymus DNA resulted in the formation of an additional adduct identified as N-(deoxyguanosin-8-yl)-1-aminopyrene (dG-C8-AP). 3. 1-Nitropyrene 9,10-oxide reacted with calf thymus DNA to give an adduct pattern similar to that observed with 1-nitropyrene 4,5-oxide. Incubation of 1-nitropyrene 9,10-oxide with CHO cells resulted in the formation of the same adducts along with dG-C8-AP. 4. dG-C8-AP and N-(deoxyguanosin-8-yl)-1-amino-x-nitropyrene (x = 3, 6 or 8; dG-C8-ANP) were detected in injection site DNA from Sprague-Dawley rats treated with 1-nitropyrene. In mammary gland DNA, dG-C8-AP and an unidentified adduct were found. dG-C8-ANP was the only DNA adduct detected in the livers of newborn CD-1 mice and the lungs of A/J mice dosed with 1-nitropyrene.
 ...
PMID:Metabolic activation of 1-nitropyrene to a mammalian cell mutagen and a carcinogen. 144 3

Nitrated polycyclic aromatic hydrocarbons are wide-spread environmental pollutants that have been detected in photocopier toners, airborne particulates, coal fly ash, and diesel engine exhaust emissions. 1-Nitropyrene, a representative nitropolycyclic aromatic hydrocarbon present in diesel particulates, is a mutagen in Salmonella typhimurium and a tumorigen in laboratory animals. The activation of 1-nitropyrene to a bacterial mutagen has been attributed to nitroreduction; however, the metabolic pathways involved in its metabolism to a tumorigen are not known, but may involve nitroreduction, ring oxidation, or a combination of the two. In these experiments, we examined the importance of ring oxidation in the activation of 1-nitropyrene (99.85 to 99.98 percent 1-nitropyrene, 0.15 to 0.02 percent 1,3-, 1,6-, and 1,8-dinitropyrene by mass spectral analyses) to a mammalian-cell mutagen and carcinogen. Chinese hamster ovary cells were used to assess the mutagenicity of ring-oxidized 1-nitropyrene metabolites. In the absence of a rat liver 9,000 x g supernatant, 6-hydroxy-1-nitropyrene, 1-nitropyrene-9,10-oxide, and pyrene-4,5-oxide were the most mutagenic compounds tested. 3-Hydroxy-1-nitropyrene, 8-hydroxy-1-nitropyrene, and 1-nitropyrene-4,5-oxide were weaker mutagens, whereas pyrene and 1-nitropyrene were essentially nonmutagenic. The order of mutagenic potency with S9 was: 1-nitropyrene-4,5-oxide greater than 6-hydroxy-1-nitropyrene approximately 1-nitropyrene-9,10-oxide greater than 1-nitropyrene approximately 3-hydroxy-1-nitropyrene approximately 8-hydroxy-1-nitropyrene greater than pyrene approximately pyrene-4,5-oxide, with the last two compounds being nearly nonmutagenic. The epoxide hydrase inhibitor 1,2-epoxy-3,3,3-trichloropropane increased the mutation frequency fivefold. In addition, guinea pig liver microsomes and Aroclor-induced rat liver microsomes, which increased the formation of 1-nitropyrene-4,5-oxide and 1-nitropyrene-9,10-oxide, increased the mutagenic response. Incubation of 1-nitropyrene-4,5-oxide with calf thymus DNA resulted in the formation of three DNA adducts. A similar adduct pattern was observed when Chinese hamster ovary cells were incubated with the oxide. Inclusion of a nitroreductase, xanthine oxidase, in the in vitro incubations resulted in the formation of an additional adduct identified as N-(deoxyguanosin-8-yl)-1-aminopyrene. This adduct was not observed in Chinese hamster ovary cells treated with 1-nitropyrene-4,5-oxide. 1-Nitropyrene-9,10-oxide reacted with calf thymus DNA to give an adduct pattern similar to that observed with 1-nitropyrene-4,5-oxide. The distribution of adducts was not affected by conducting the reactions in the presence of xanthine oxidase.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Role of ring oxidation in the metabolic activation of 1-nitropyrene. 177 57

The 32P-postlabeling technique was used to qualitatively establish the pattern of DNA adduct formation in mammary tissue and liver following administration of 1-nitropyrene to female Sprague-Dawley rats. 1-Nitropyrene (100 mg/kg b.w.) was administered by gavage in trioctanoin and the rats were sacrificed 24 h later. DNA was isolated from mammary fat pads and liver, enzymatically hydrolyzed to deoxyribonucleoside-3'-monophosphates and then converted to [5'-32P]3',5'-bisphosphates. The polyethyleneimine-cellulose (PEI-cellulose) TLC 32P-fingerprints revealed the presence of multiple putative adducts in the mammary fat pads and in the livers. To investigate the role of nitroreduction in the formation of these adducts, calf thymus DNA was incubated with [3H]1-nitropyrene in vitro in the presence of xanthine oxidase. The DNA was isolated and analyzed by the 32P-postlabeling technique. A major adduct spot was detected and confirmed as N-(deoxyguanosin-8-yl)-1-aminopyrene. This adduct cochromatographed with a minor in vivo adduct of DNA obtained from mammary fat pads and livers. However, the major adducts detected in vivo did not appear to originate from simple nitroreduction of 1-nitropyrene. The results of this study suggest that other metabolic pathways, such as ring oxidation, or ring oxidation followed by nitroreduction, may be responsible for the putative 1-nitropyrene-DNA adducts observed in mammary fat pads and livers of female Sprague-Dawley rats.
 ...
PMID:32P-postlabeling analysis of 1-nitropyrene-DNA adducts in female Sprague-Dawley rats. 291 May 23

1-Nitropyrene, 1-nitrosopyrene and 1-aminopyrene were investigated for their ability to induce covalently bound DNA adducts in calf thymus DNA and Chinese hamster lung fibroblasts. Xanthine oxidase catalysed the induction of one major and one minor DNA adduct in 1-nitropyrene- or 1-nitrosopyrene-treated calf thymus DNA, whilst 1-aminopyrene was inactive. These compounds did not form detectable DNA adducts in the absence of xanthine oxidase. The major DNA adduct produced by 1-nitropyrene and 1-nitrosopyrene in calf thymus DNA co-migrated on h.p.l.c., and the structure was consistent with that previously described by others as N-(deoxyguanosin-8-yl)-1-aminopyrene. The compounds were investigated for their ability to form DNA adducts in Chinese hamster lung fibroblasts. 1-Nitropyrene (5.2 pmol/mg DNA/h) and 1-nitrosopyrene (129 pmol/mg DNA/h) formed a single DNA adduct in Chinese hamster lung cells which co-eluted on h.p.l.c. with the C-8 deoxyguanosine adduct isolated from 1-nitropyrene-treated calf thymus DNA. 1-Nitrosopyrene was the most efficient compound investigated for the production of the C-8 guanine adducts. In contrast, 1-aminopyrene (14.7 pmol/mg DNA/h) induced the formation of a DNA adduct which did not co-elute with the C-8 guanine adduct. The data presented here suggest that 1-nitropyrene and 1-aminopyrene are metabolized to reactive intermediates which form different DNA adducts in Chinese hamster lung fibroblasts.
 ...
PMID:The induction of DNA adducts in mammalian cells exposed to 1-nitropyrene and its nitro-reduced derivatives. 333 73

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.
 ...
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.
 ...
PMID:Evidence for N-(deoxyguanosin-8-yl)-1-aminopyrene as a major DNA adduct in female rats treated with 1-nitropyrene. 383 6

1-Nitropyrene (1-NP), a common environmental pollutant, is a mutagen and tumorigen. Nitroreduction is a major pathway by which 1-NP is metabolized. In order to study the mutational specificity of reductively activated 1-NP, single-stranded M13mp18 DNA was treated with tritium-labeled 1-nitrosopyrene in the presence of ascorbic acid to generate N-hydroxy-1-aminopyrene in situ. HPLC analysis of the treated DNA, following enzymatic digestion, showed that > 95% of tritium was located in one major adduct, N-(deoxyguanosin-8-yl)-1-aminopyrene. Transfection of these adducted M13 DNA in Escherichia coli indicated a dose-dependent reduction in viability with concomitant enhancement in mutagenesis in the lacZ gene fragment. Without SOS functions, the major type of mutation was C-->T transition (48%). Further studies have shown that cytosine deamination occurred during ascorbic acid-induced nitroreduction, which was likely responsible for the C-->T transitions. Deamination of cytosine alco occurred at a significant frequency when nitroreduction of either 1-NP or 1-nitrosopyrene was catalyzed by xanthine oxidase, a mammalian nitroreductase.
 ...
PMID:Reductive metabolism of 1-nitropyrene accompanies deamination of cytosine. 769 38

1-Nitropyrene, the most abundant nitro-polycyclic aromatic hydrocarbon in the environment, is a known mammalian and bacterial mutagen and a tumorigen in animals. Early studies on DNA adduct characterization for 1-nitropyrene identified N-(deoxyguanosin-8-yl)-1-aminopyrene as the major product from the modification of calf thymus DNA with N-hydroxy-1-aminopyrene, the activated metabolite from nitroreduction of 1-nitropyrene. In this paper, we report the identification of two N2-deoxyguanosinyl adducts, in addition to N-(deoxyguanosin-8-yl)-1-aminopyrene, formed from the reaction of N-hydroxy-1-aminopyrene, prepared in situ, with calf thymus DNA. These DNA adducts were identified as 6-(deoxyguanosin-N2-yl)-1-aminopyrene and 8-(deoxyguanosin-N2-yl)-1-aminopyrene. The two N2-deoxyguanosinyl adducts were also identified in an ascorbic acid-catalyzed activation of 1-nitrosopyrene and in the mammary gland of female Sprague-Dawley rats administered 1-nitropyrene. The DNA adducts were also formed when 1-nitropyrene was metabolized by xanthine oxidase in the presence of calf thymus DNA, and when 1-nitropyrene was activated by rat liver microsomes and cytosols, as well as from DNA isolated from Salmonella typhimurium suspension cultures incubated with 1-nitropyrene.
 ...
PMID:Identification of two N2-deoxyguanosinyl DNA adducts upon nitroreduction of the environmental mutagen 1-nitropyrene. 776 11