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)

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)
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PMID:Role of ring oxidation in the metabolic activation of 1-nitropyrene. 177 57

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.
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PMID:Oxidative microsomal metabolism of 1-nitropyrene and DNA-binding of oxidized metabolites following nitroreduction. 375 82