Disease relevance of CCRIS 2212

• Induction of squamous cell carcinoma in the rat lung by 1,6-dinitropyrene [1].
• 1,6-Dinitropyrene: mutagenicity in Salmonella and carcinogenicity in BALB/c mice [2].
• The effect of 2-aminofluorene (2-AF) on the toxicity of 2-aminoanthracene (2-AA) and 1,6-dinitropyrene (1,6-DNP) was studied in N-acetyltransferase-proficient V79-NHr1A2 cells genetically engineered for the expression of cytochrome P4501A2, and in wild-type V79-NH cells [3].
• Active H-ras and N-ras in rat fibrosarcomas induced by 1,6-dinitropyrene [4].
• Metabolic activation of 1-nitropyrene and 1,6-dinitropyrene by nitroreductases from Bacteroides fragilis and distribution of nitroreductase activity in rats [5].

High impact information on CCRIS 2212

• In these experiments, we have investigated the use of DNA adducts and T-lymphocyte mutations of 1,6-dinitropyrene as biomarkers for exposure to diesel emissions [6].
• In contrast to the case of 1,3-dinitropyrene, the inactivation of 1,6-dinitropyrene is well correlated with levels of cytochrome P-450NF (P-450 IIIA4, nifedipine oxidase) and its catalytic activities [7].
• Kinds of mutations found when a shuttle vector containing adducts of 1,6-dinitropyrene replicates in human cells [8].
• 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 [9].
• DNA binding of both 1-nitropyrene and 1,6-dinitropyrene in vitro was 2-fold higher when using cytosol from 1-nitropyrene-pretreated rats [9].

Biological context of CCRIS 2212

• Induction of DNA repair in human and rat hepatocytes by 1,6-dinitropyrene [10].
• The ability of 1,6-dinitropyrene and 1,8-dinitropyrene to induce chromosome aberrations has been examined in a rat epithelial cell line (RL4) [11].
• We have investigated the cytogenetic effect of 1,6-dinitropyrene (1,6-DNP) in Chinese hamster V79 cells [12].
• In vivo mutagenesis in the lungs of gpt-delta transgenic mice treated intratracheally with 1,6-dinitropyrene [13].
• The effects of 1,6-dinitropyrene (1,6-DNP) on the fidelity of cell division were studied in the transformed human fibroblast cell line MRC5VA [14].

Anatomical context of CCRIS 2212

• These findings indicate that concentrations of 1,6-dinitropyrene that produce a dose-dependent induction of lung tumors also result in a dose-dependent formation of DNA adducts and induction of lymphocyte mutations but that the dose-response curves for DNA binding and mutations are different [15].
• 1,6-Dinitropyrene and 1-nitropyrene induced unscheduled DNA synthesis in epithelial cells of in vitro cultured human bronchi, as did diol-epoxides of benzo[a]pyrene, while benzo[a]pyrene itself was inert [16].
• 1,6-Dinitropyrene (DNP) was found to be an extremely potent genotoxicant in metabolically competent primary cultures of human and rat hepatocytes [10].
• Genotoxicity of 1,3- and 1,6-dinitropyrene: induction of micronuclei in a panel of mammalian test cell lines [17].
• In these experiments, 1,6-dinitropyrene was implanted into the lungs of rats according to a protocol known to induce lung tumors; the DNA adducts were characterized and quantified in target (lung) and surrogate (liver, white blood cells, and spleen lymphocytes) tissues [18].

Associations of CCRIS 2212 with other chemical compounds

• Liver or mammary gland cytosol with acetyl CoA yielded mainly N-(deoxyguanosin-8-yl)-2-amino-7-NF from 2,7-diNF at >30 adducts/10(6) nucleotides, levels comparable to those from 1,6-dinitropyrene and 4- or 49-fold greater than the respective levels without acetyl CoA [19].
• Analysis of mutations in the K-ras and p53 genes of lung tumors and in the hprt gene of 6-thioguanine-resistant T-lymphocytes from rats treated with 1,6-dinitropyrene [20].
• The activity of six Chinese medicinal herbs against the environmental mutagens and carcinogens benzo[a]pyrene (B[a]P), 1,6-dinitropyrene (1,6-diNP) and 3,9-dinitrofluoranthene (3,9-diNF) was determined [21].
• The major reduced metabolite of 1,6-dinitropyrene in aerobic incubations with rat liver cytosol is 1-nitro-6-nitrosopyrene, and further reduction of this metabolite results in formation of DNA-reactive species [22].
• 5-hydroxymethyl-2'-deoxyuridine was detected in DNA from each of these tissues, and the levels of this oxidized nucleoside were higher in the mammary glands and livers of 1,6-dinitropyrene-treated rats [23].

Gene context of CCRIS 2212

• The ability of 1,6-dinitropyrene to induce chromosome damage in peripheral human lymphocyte cultures has been demonstrated [24].
• We measured the response of HepG2 cells to the classic cytochrome (cyt.) P-450 inducers 3-methylcholanthrene (3-MC) and phenobarbital (PB), by evaluating oxidative and/or reductive metabolism of the nitroarenes, 1-NP and 1,6-dinitropyrene (1,6-DNP), in control and induced cells [25].
• Cell lines such as hamster V79, BHK, rat hepatoma H4IIEC3G- or fibroblast 208F, which are sensitive to 1,6-dinitropyrene (1,6-DNP), possess high transferase activities ranging from 120-270 nmol/min x mg protein [26].
• Arylamine N-acetyltransferase activities in cell lines of mouse, rat, hamster and man differing in their sensitivity to 1,6-dinitropyrene [26].
• After a similar treatment with 1,6-dinitropyrene, mutations were assayed at the hprt locus in spleen T lymphocytes for up to 51 weeks [18].

Analytical, diagnostic and therapeutic context of CCRIS 2212

• 1,6-Dinitropyrene has been shown to be a strong hepatocarcinogen but a weak lung carcinogen in this same bioassay [27].
• One week after treatment with 0.3, 1, 3, 10, 30, 100, or 150 micrograms of 1,6-dinitropyrene, dose-responsive DNA binding was measured in lung and liver with binding in the lung being 10-fold higher than in the liver [15].
• The activated oncogenes in rat fibrosarcomas induced by subcutaneous injection of 1,6-dinitropyrene (1,6-DNP), an environmental mutagen-carcinogen, were examined by NIH3T3 cell transfection assay and Southern blot analysis [4].
• The concentrations of 1-nitropyrene (1-NP) and 1,6-dinitropyrene (1,6-diNP) in these extracted materials were also measured after nitroreduction by high pressure liquid chromatography [28].
• After a single intraperitoneal injection of 1-nitropyrene, covalent DNA binding 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 [29].

References