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At least 19 recordsLinked to original sources
PubMed1988

The conjugation of 4-nitroquinoline 1-oxide, a potent carcinogen, by mammalian glutathione transferases. 4-Nitroquinoline 1-oxide conjugation by human, rat and mouse liver cytosols, extrahepatic organs of mice and purified mouse glutathione transferase isoenzymes.

The conjugation of 4-nitroquinoline 1-oxide with GSH by human, rat and mouse liver cytosols, by purified mouse GSH transferases and by extrahepatic organ cytosols of male and female mice was investigated. 4-Nitroquinoline 1-oxide was as effectively conjugated by human liver cytosol as was 1-chloro-2,4-dinitrobenzene, at a substrate concentration of 0.1 mM. Mouse isoenzymes composed of Yb1 and Yf subunits exhibited high activity towards 4-nitroquinoline 1-oxide. Human, rat and mouse hepatic activities towards this substrate correlated with the hepatic isoenzyme compositions.

4-Nitroquinoline-1-oxide↗
PubMed1988

Polyclonal antibodies to DNA modified with 4-nitroquinoline 1-oxide: application for the detection of 4-nitroquinoline 1-oxide-DNA adducts in vivo.

Antibodies against 4-nitroquinoline 1-oxide (4NQO) adducts were elicited in rabbits immunized with 4NQO-modified DNA complexed with methylated bovine serum albumin. In enzyme-linked immunosorbent assay (ELISA), the antibodies could recognize either denatured or native 4NQO-modified DNA, but not unmodified DNA, DNA modified with other carcinogens or free 4NQO derivative. Modification levels as low as 5 mumol of adduct per one mole DNA nucleotide (5 adducts/10(6) nucleotides) can be easily detected by the competitive ELISA. Indirect immunofluorescence staining by anti 4NQO-DNA antibody indicated that the antibodies bound specifically to the nuclei of normal human skin fibroblast cells treated with 4NQO. The intensity of fluorescence was proportional to the dose of 4NQO used to treat the cells, and the fluorescence-positive cells could be detected after treatment with 0.25 microM 4NQO (which resulted in the formation of 10(4) adducts per cell). Applying the competitive ELISA to the quantitation of DNA-adducts in rats treated with 4NQO, it was confirmed that the sensitivity of immunochemical assays was equivalent to that of isotopic assays. These methods should be helpful in studies on the formation of adducts and their removal in cells and tissues.

4-Nitroquinoline-1-oxide↗
PubMed1975

Breakage of a DNA-protein complex induced by 4-nitroquinoline 1-oxide, 4-nitropyridine 1-oxide, and their derivatives in cultured mouse fibroblasts.

The effects of a number of 4-nitroquinoline 1-oxide and 4-nitropyridine 1-oxide derivatives, with varying carcinogenic potencies, on the scission of proteins linking DNA were studied in cultured mouse fibroblasts, strain L-P-3. With twenty-two 4-nitroquinoline 1-oxide derivatives and twelve-4-nitroquinoline 1-oxide derivatives tested, an excellent correlation was found between the scission effect of each compound and its carcinogenicity. All carcinogens, whether strong or weak, showed positive results in the scission test. Strong carcinogens such as 4-nitroquinoline 1-oxide, 2-methyl-4-nitroquinoline 1-oxide, 6-methyl-4-nitroquinoline 1-oxide, 6-chloro-4-nitroquinoline 1-oxide,and 4-hydroxyaminoquinoline 1-oxide induced the scission at a low concentration of 1 x 10-5 M, while weak carcinogens such as 3-methyl-4-nitroquinoline 2-oxide, 6-n-butyl-4-nitroquinoline 1-oxide, 6-tert-butyl-4-nitroquinoline 1-oxide, 6-n-hexyl-4-nitroquinoline 1-oxide, and 6-carboxy-4-nitroquinoline 1-oxide only produced the same effect a dose levels higher than 5 x10-5 M. On the other hand, some noncarcinogenic derivatives such as 8-nitroquinoline 1-oxide, 4-hydoxy-quinoline 1-oxide, 4-aminoquinoline 1-oxide, and 6-nitroquinoline could not induce the scission, while other noncarcinogens such as 3-nitroquinoline 1-oxide, 5-nitroquinoline 1-oxide, and 5-nitroquinoline did induce scission at concentrations higher than 1 x 10-4 M. Throughout these tests the effective concentrations of active compounds were generally much lower than the concentration at which the compounds were cytotoxic. The implication of the results and the feasibility of the present method of analysis as a screening procedure for potential carcinogens and muagens are discussed.

Animals↗
PubMed2004

The yeast phosphotyrosyl phosphatase activator protein, yPtpa1/Rrd1, interacts with Sit4 phosphatase to mediate resistance to 4-nitroquinoline-1-oxide and UVA.

We previously reported the isolation of mutants hypersensitive to the genotoxic agent 4-nitroquinoline-1-oxide, a potent inducer of oxidative stress. One of the mutants was defective in a gene designated yPTPA1, encoding a protein related to the human phosphotyrosyl phosphatase activator hPTPA, which is believed to play a role in activating the serine/threonine phosphatase PP2A. Yeast yptpa1Delta mutants are also sensitive to the UVA component of sunlight known to produce reactive oxygen species, suggesting a role for yPtpa1 in oxidative stress response. We now report the characterization of another 4-nitroquinoline-1-oxide-sensitive mutant, EBY20. We show that this mutant is defective in the SIT4 gene encoding a catalytic subunit of the PP2A phosphatases and that sit4Delta mutants exhibit hypersensitivity to 4-nitroquinoline-1-oxide and UVA, but not to UVC at 254 nm. Like the yptpa1Delta mutants, sit4Delta mutants are also defective in the repair of 4-nitroquinoline-1-oxide-induced DNA lesions. Genetic analysis revealed that both yPtpa1 and Sit4 function in the same pathway to protect cells against the lethal effects of 4-nitroquinoline-1-oxide and UVA. Moreover, we demonstrate that yPtpa1-affinity columns specifically retain Sit4, confirming a previous report that these two proteins indeed belong to a complex. Cellular localization studies using GFP-tagged proteins reveals that yPtpa1 is localized to the cytoplasm and the nucleus, while the Sit4 protein shows an intense staining spot in the cytoplasm and diffused staining in this organelle. We suggest that the yPtpa1-Sit4 complex may participate in a novel mechanism that mediates repair of oxidative DNA damage caused by 4-nitroquinoline-1-oxide and UVA.

4-Nitroquinoline-1-oxide↗
PubMed1989

Identification of the glutathione conjugate of 4-nitroquinoline 1-oxide formed in the reaction catalyzed by murine glutathione transferases.

The product of the enzyme-catalyzed conjugation of glutathione and 4-nitroquinoline 1-oxide was isolated and its structure determined by MS and NMR. The results indicate that the cysteine sulfur of glutathione replaces the nitro group of 4-nitroquinoline 1-oxide in the reaction with the formation of 4-(glutathion-S-yl)-quinoline 1-oxide. No evidence was found for the binding of glutathione to any other position of 4-nitroquinoline 1-oxide or through any group other than the cysteine sulfur.

4-Nitroquinoline-1-oxide↗
PubMed1981

Coordinate mutation and transformation of mouse fibroblasts: induction by nitroquinoline oxide and modulation by caffeine.

Mutation and malignant transformation were followed in the same cells. Mouse fibroblasts (C3H 10T 1/2) were mutated and transformed by 4-nitroquinoline-1-oxide with similar, approximately linear dose-responses. The presence of caffeine immediately after exposure to 4-nitroquinoline-1-oxide potently inhibited mutation and transformation at high but not at low doses of 4-nitroquinoline-1-oxide. Whilst the coordinate induction of mutation and transformation could be explained by both a common target (DNA) or a common reactive species hitting several targets, the identical modulation by a DNA repair inhibitor of both end points suggests fundamental similarities in the nature of the lesions leading to mutation and transformation and in the processing of these lesions, implying DNA as target and mutation as one (but not necessarily the sole) required step in transformation.

4-Nitroquinoline-1-oxide↗
PubMed1986

Inhibition of enzymic incision of thymine dimers by covalently bound guanine adducts of 4-nitroquinoline-1-oxide in DNA.

The effects of the presence in DNA of covalently bound guanine adducts of the carcinogen 4-nitroquinoline-1-oxide on the pyrimidine dimer-DNA glycosylase, purified from bacteriophage T4-infected Escherichia coli, were investigated. E. coli DNA, labeled in thymine, photosensitized by silver nitrate, and irradiated by 254 nm monochromatic light, was the substrate. 4-Nitroquinoline-1-oxide was reduced to 4-hydroxyaminoquinoline-1-oxide and then reacted with irradiated DNA in the presence of seryl-AMP, yielding covalently bound adducts in DNA. These were assayed by high performance liquid chromatography. Enzyme activity was assayed by measuring release of labeled free thymine from directly photoreversed DNA after the reaction. Glycosylase activity was reduced against carcinogen-modified DNA, with the Vmax 38% of that against the control DNA; the Km was unaffected. Therefore, as with other modified purines, 4-nitroquinoline-1-oxide guanine modifications can reduce enzymic incision at thymine dimers. Left unrepaired, pyrimidine dimers are both mutagenic and carcinogenic. This is consistent with the possibility that interference with enzymic initiation of DNA excision repair of UV damage may be an indirect mechanism of mutagenesis by stable carcinogen-DNA adducts.

4-Nitroquinoline-1-oxide↗
PubMed1984

Detection of in vivo DNA repair synthesis in mouse liver and lung induced by treatment with benzo(a)pyrene or 4-nitroquinoline 1-oxide.

We examined in vivo DNA repair synthesis in liver and lung of A/HeJ mice treated with benzo(a)pyrene (BP) or 4-nitroquinoline 1-oxide. To differentiate between the removal of carcinogen metabolite:DNA adducts due to cell turnover and DNA repair, we measured unscheduled DNA synthesis (UDS) in the nonreplicating DNA fraction. Mice were exposed to bromodeoxyuridine pellets 1 hr prior to carcinogen treatment. Immediately following carcinogen exposure, mice received 4 hourly i.v. doses of [3H]thymidine. Mice were sacrificed 5 hr post-carcinogen treatment, and DNA was isolated. Purified DNA was then separated into newly replicated and nonreplicated DNA by ultracentrifugation in alkaline CsCl gradients. BP induced UDS in the liver at p.o. doses of 0.3 and 3.0 mg/mouse, whereas we failed to detect UDS in the lung. However, 4-nitroquinoline 1-oxide, another lung carcinogen, induced a definite repair response in the lung but not in the liver. It is not clear why mouse lung cells have the capacity to repair 4-nitroquinoline 1-oxide-induced damage to DNA and not the damage induced by BP, since both of these lung carcinogens form bulky adducts with DNA. These results demonstrate that (a) the in vivo disappearance of BP metabolite:DNA adducts from the lung of the A/HeJ mouse is due to cell turnover, whereas the disappearance of adducts from the liver is due, in part, to DNA repair and (b) induction of in vivo UDS after treatment with two different lung carcinogens is both tissue and carcinogen dependent in this mouse strain.

4-Nitroquinoline-1-oxide↗
PubMed1975

Recovery of a DNA-protein complex in cultured mammalian cells from damage caused by 4-nitroquinoline 1-oxide.

Treatment of FM3A cells with 4-nitroquinoline 1-oxide caused a decrease in the sedimentation velocity of a DNA-protein complex, but did not cause a dissociation of the complex, as revealed by neutral sucrose gradient centrifugation. Microscopic autoradiography of the complex spread on a Millipore filter, demonstrated that treatment of the cells with 4-nitroquinoline 1-oxide, or of the complex with Pronase E, gave rise to a relaxed mass of DNA fibers, in contrast to a compact mass of DNA from control cells. The damage to the DNA-protein compelx was repaired completely by incubation of the cells in a medium without 4-nitroquinoline 1-oxide. The following metabolic inhibitors had no effect on the repair of the complex: inhibitors of nucleic acid synthesis, alpha-amanitine, cordycepin, 2-mercapto-1-(beta-4-pyridethyl)benzimidazol, 1-beta-D-arabinofuranosylcytosine, 5-fluorodeoxyuridine, and hydroxyurea; inhibitors of protein synthesis, cycloheximide and puromycin; an inhibitor of the dark repair process in a variety of biological systems, caffeine; inhibitors of the microtubular and microfilament system, Colcemid and cytochalasin B, respectively; and inhibitors of energy metabolism, 2,4-dinitrophenol, KCN, iodoacetic acid, ouabain, and an atmosphere of nitrogen. Acriflavine and actinomycin D, which are known to intercalate into DNA, caused a decrease in the sedimentation velocity of the DNA-protein complex; therefore, the effects of these agents on the recovery process remained unsolved. The repair process of the complex was, however, demonstrated to be temperature dependent. The process was inhibited at 10 degrees, retarded at 28 degrees, but accelerated at 40 degrees as compared with the rate at 37 degrees.

4-Nitroquinoline-1-oxide↗
PubMed1994

Oxygen dependence of the cytotoxicity and metabolic activation of 4-alkylamino-5-nitroquinoline bioreductive drugs.

The cytotoxic potency of 4-alkylamino-5-nitroquinoline drugs in AA8 cell cultures is enhanced up to 60-fold under hypoxia, with wide variations in selectivity for hypoxic cells observed for different members of this series. This study uses three representative 5-nitroquinolines to examine whether these differences in hypoxia-selective cytotoxicity are cell line specific, and to explore quantitatively the oxygen dependence of the cytotoxicity and metabolism of these compounds. The parent compound 5NQ, its 5NQ, its 8-methyl analogue (8Me5NQ) and the 8-methylamino analogue (8NHMe-5NQ) each showed similar hypoxic selectivity (ratio of concentration x time for 90% kill for zero versus 20% oxygen of 13-18-, 30-69- and 1.2-1.4-fold respectively in the three cell lines tested (AA8 Chinese hamster ovary, EMT6/Ak mouse mammary tumour and FME human melanoma). The cytotoxicity and metabolism (covalent binding) of radiolabelled 8Me-5NQ was investigated in AA8 cultures over a range of oxygen tensions (0-95%). The oxygen tension in solution required for 50% inhibition of log cell kill or adduct formation observed under anoxia (C50) was 0.01 and 0.02% oxygen respectively, suggesting that bioreductive alkylation is the mechanism of 8Me-5NQ toxicity. The K-value (oxygen concentration for cytotoxic potency equal to the mean of the potencies at zero and infinite oxygen) was similar (0.02% oxygen). Calculations based on measured rate constants for formation of the nitroradical anion of 8Me-5NQ and rates of radical loss through disproportionation or reaction with oxygen, predict a K-value for 8Me-5NQ of 0.025% oxygen, in good agreement with the experimentally determined value. Modelling of cell killing expected by the combination of 8Me-5NQ plus radiation suggested that tumour cells at intermediate oxygen tensions (0.01-1%) will be partially resistant to this treatment, and would limit the use of these 5-nitroquinolines in combination with radiation, unless sufficient drug could be delivered to cause extensive killing in the anoxic compartment.

Animals↗