Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-Nitropyrene, the predominant nitropolycyclic aromatic hydrocarbon found in diesel exhaust, is a mutagen and tumorigen. 1,6-Dinitropyrene is present in diesel exhaust in much smaller quantities than 1-nitropyrene, but is much more mutagenic and carcinogenic. In an attempt to understand this difference in biological potencies, we have compared the extent of DNA binding by these two nitropyrenes in vivo. We have also determined the effect of 1-nitropyrene pretreatment upon the induction of nitroreductases and the subsequent DNA binding by both 1-nitropyrene and 1,6-dinitropyrene. Covalent DNA binding by 1-nitropyrene could not be detected in vivo; however, 1,6-dinitropyrene formed N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene as the major DNA adduct in rat liver, kidney, urinary bladder and mammary gland, with the highest levels being found in the bladder. The capability of liver microsomes to catalyze the oxidative metabolism of 1-nitropyrene was unchanged after treating rats with 8 mg/kg 1-nitropyrene. Cytochrome P-450, NADPH-cytochrome P-450 reductase and cytochrome b5 levels were also unchanged, while slight increases were detected in NADH-cytochrome b5 reductase and epoxide hydrase activities. Liver cytosolic and microsomal nitroreductase activities toward both 1-nitropyrene and 1,6-dinitropyrene were increased 2-fold, and cytosolic nitrosoreductase activity toward 1-nitrosopyrene and 1-nitro-6-nitrosopyrene was elevated by approximately 20%. DNA binding of both 1-nitropyrene and 1,6-dinitropyrene in vitro was 2-fold higher when using cytosol from 1-nitropyrene-pretreated rats. However, pretreatment of rats with 1-nitropyrene only slightly increased the amount of in vivo DNA binding by 1,6-dinitropyrene except in kidney where there was a 60% increase. These results indicate that although nitroreduction is involved in DNA adduct formation by 1,6-dinitropyrene, additional factors (e.g. O-acetylation) limit the extent of DNA binding in vivo.
Carcinogenesis 1988 Mar
PMID:DNA binding by 1-nitropyrene and 1,6-dinitropyrene in vitro and in vivo: effects of nitroreductase induction. 334 77

1,6-Dinitropyrene and 1,8-dinitropyrene are environmental contaminants which are mutagenic in bacteria and cultured mammalian cells. Since nitroreduction, and possibly O-acetylation, have been implicated in the metabolic activation of these compounds, the reduced intermediates, 1-nitro-6-nitrosopyrene and 1-nitro-8-nitrosopyrene, were synthesized and their mutagenicity examined in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Nitration of 1-acetylaminopyrene yielded a mixture of 1-acetylamino-6-nitropyrene and 1-acetylamino-8-nitropyrene, which was separated by flash chromatography. Following deacetylation, the amino-nitropyrenes were oxidized to the desired nitronitrosopyrenes with m-chloroperoxybenzoic acid. Both nitronitrosopyrenes showed similar levels of mutagenicity in S. typhimurium strain TA98 and a nitroreductase-deficient analogue, TA98NR, but much lower activity in the esterificase-deficient strain, TA98/1,8-DNP6, which suggested that reduced metabolites require further activation by O-acetylation. In contrast, the analogous compound, 1-nitrosopyrene, was equally mutagenic in all three strains while its parent compound, 1-nitropyrene, demonstrated a much reduced mutagenicity in strain TA98NR. In CHO cells, 1-nitropyrene was not mutagenic and the dinitropyrenes were only weakly active, while all three nitrosopyrene derivatives were highly mutagenic. These data support the hypothesis that nitrated pyrenes are metabolized to mutagens through nitroreduction. In Salmonella the limiting step in the metabolic activation of 1-nitropyrene appears to be the initial reduction to 1-nitrosopyrene, while with the dinitropyrenes subsequent esterification of the reduced intermediates seems critical. With CHO cells, the initial reduction to nitroso derivatives is the limiting step for all nitropyrenes, and esterification does not appear to occur in the activation sequence.
Carcinogenesis 1986 Jan
PMID:Synthesis and mutagenicity of 1-nitro-6-nitrosopyrene and 1-nitro-8-nitrosopyrene, potential intermediates in the metabolic activation of 1,6- and 1,8-dinitropyrene. 351 Jul 51

1,6-Dinitropyrene elicits a potent mutagenic response in a range of microorganisms in the absence of auxiliary metabolism (S9 mix). This activity is considered to be dependent upon nitroreductase enzymes endogenous to the marker organism producing electrophilic species from one or both of the nitro groups. In order to evaluate this suggestion 1,6-diaminopyrene has been synthesised, characterized and found to elicit a mutagenic response in strain TA98 of Salmonella typhimurium, but only when evaluated in the presence of S9 mix. The active dose-range of the diamino compound was 10(4) times higher than that of the parent dinitro compound.
Carcinogenesis 1983
PMID:Synthesis of 1,6-diaminopyrene from 1,6-dinitropyrene and its S9 dependent mutagenicity to S. typhimurium. 634 21

An assay for measuring chemically-induced DNA repair in primary cultures of rat tracheal epithelial (TE) cells has been developed and characterized. Chemical exposure may be either in vitro or in vivo. Epithelial cells were removed from the trachea by protease digestion, allowed to attach to collagen-coated glass slides, and incubated with [3H]-thymidine. DNA repair was assessed as unscheduled DNA synthesis by quantitative autoradiography. The direct acting genotoxicants methyl methanesulfonate (100 microM) and N-methyl-N'-nitro-N-nitrosoguanidine (10 microM) yielded a positive response in vitro. 1,6-Dinitropyrene (DNP) (0.05 microM) and dimethylnitrosamine (DMN) (1 mM) were also positive in vitro demonstrating that TE cells have the capacity to metabolically activate these compounds. 2-Acetylaminofluorene (AAF), aflatoxin B1 (AFB1), and benzo[a]pyrene (BP) were all negative in vitro, suggesting organ specific patterns of metabolic activation. DMN, which has been shown to induce DNA repair in TE cells following exposure by inhalation, was negative when administered by gavage. 1,6-DNP, BP and AAF did not induce DNA repair or alter the fraction of cells in S-phase when administered by gavage. Formaldehyde did not induce DNA repair or increase the fraction of cells in S-phase in TE cells following either in vivo exposure by inhalation (0.47, 2, 5.9 or 14.8 p.p.m. for 1, 3 or 5 days) or exposure of the cultured cells in vitro (100 microM). This assay provides the means to assess the genotoxic potential of environmental chemicals in the epithelial cells of the respiratory system.
Carcinogenesis 1984 Jun
PMID:Assessment of chemically-induced DNA repair in rat tracheal epithelial cells. 672 86

1,6-Dinitropyrene (1,6DNP) and 1,8-dinitropyrene (1,8DNP) were tested for their ability to induce mitotic gene conversion at the trp 5 and his 4 loci in the yeast Saccharomyces cerevisiae JD1. Both compounds were shown to be potent inducers of gene conversion in yeast, with 1,6DNP being somewhat more active than 1,8DNP. Unusual dose-response curves were obtained in that toxicity and genetic activity decreased at the higher concentrations examined. This reduction in genetic activity may reflect a decrease in the ability of yeast cells to convert the dinitropyrenes to their mutagenic forms when the concentration of the compounds exceeds a certain level.
Carcinogenesis 1981
PMID:The genetic activity of dinitropyrenes in yeast: unusual dose response curves for induced mitotic gene conversion. 703 43