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Modification of mutagenic activities of pro-mutagens by glyco-ursodeoxycholic acid in the Ames assay.

Mutagenicity, co-mutagenicity and anti-mutagenicity of glycoursodeoxycholic acid (GUDCA) were examined by the Ames assay using Salmonella typhimurium strain TA98 with S9. As pro-mutagens, 2-aminoanthracene (2AA), Benzo[a]pyrene (BaP), 3-amino-1-dimethyl-5H-pyrido[4, 3-b]indole (Trp-P-2), 2-amino-3-methylimidazo[4, 5-f]quinoline (IQ) and 2-amino-3, 4-dimethylimidazo[4, 5-f]quinoline (MeIQ) were used. In addition to these pro-mutagens, blue-chitin extracts of human gallbladder bile (BCE) collected from the cholecystectomized patients with cholelithiasis were used in order to investigate the role of GUDCA on mutagen(s) actually existing in human bile. It was found that GUDCA did not show mutagenicity in this test system. Concerning the modification of mutagenic activities of pro-mutagens, GUDCA showed the different directions. GUDCA acted as co-mutagen, since it enhanced the mutagenic activities of 2AA and BaP. But, acted as anti-mutagen, since it suppressed the activities of Trp-P-2, IQ and MeIQ, all of which were classified as heterocyclic amines. GUDCA also suppressed the mutagen(s) in human bile. Because of the use of blue-chitin absorbed method for testing bile mutagenicity, the chemicals involved were considered to be heterocyclic amines and other polycyclic compounds. In these we suspect the bile mutagens are heterocyclic amines. Further examination should be directed towards the investigation into the mechanism of anti-mutagenic effects of GUDCA on mutagen(s) actually existing in human bile.

Anthracenes↗

Biodegradation of PAH and DEHP micro-pollutants in mesophilic and thermophilic anaerobic sewage sludge digestion.

Anaerobic digestion for the treatment of sludge in wastewater treatment plants has been reported to produce a low organic loaded effluent with an acceptable economic cost. But in the last years, new regulations and the increasing sludge production invite us to find an alternative and/or to improve the process efficiency. Moreover, the use of the effluent as fertilizer in agriculture imposes more restrictions on digestion process product and its micropollutant contents to protect the environment. In this study, a performance of the anaerobic digestion under mesophilic and thermophilic conditions at different hydraulic retention times (HRT) is assessed and the removal efficiencies of two important compounds or family compounds (Polycyclic Aromatic Hydrocarbons, PAH, and Di-2-(Ethyl-Hexyl)-Phthalate, DEHP) are evaluated. A positive effect of thermophilic temperature was observed on both micropollutants' biodegradation. However, HRT effect also had an important role for DEHP and low molecular weighted PAH removal.

Anaerobiosis↗

Current trends in the biological monitoring of exposure to carcinogens.

The biological monitoring of exposure to carcinogens and mutagens has gained a lot of research interest recently. Biological monitoring data, in conjunction with environmental monitoring data, will provide information for the needed exposure assessment for directing preventive actions. For the reviewed carcinogens aromatic amines, benzene, ethylene oxide, aflatoxins, N-nitroso compounds, polynuclear aromatic hydrocarbons, and alkylating anticancer drugs, there are methods which are already routine in practice, whereas some promising methods are still used only for research purposes.

Aflatoxins↗

Effects of derivatives of NGP 1-01, a putative calcium channel antagonist, on electrically stimulated guinea-pig papillary muscle.

In earlier work we have reported calcium antagonistic properties for the polycyclic compound NGP 1-01. We now have derivatized NGP 1-01 by side-chain substitution to obtain ten novel aromatic and aliphatic imino-keto and amino-ether compounds. Electrophysiological tests were conducted on these compounds using isolated guinea-pig papillary muscle preparations to record calcium-mediated (slow) action potentials (APs). The lipophilicities of the compounds, expressed as chromatographically determined RM values, were measured and the molecular surface areas calculated. Several derivatives showed increased activity compared with NGP 1-01. All compounds with aromatic side-chains (benzyl, phenethyl, phenylpropyl) were active (concentrations required for complete suppression of the AP varied between 1 x 10(-5) M and 5 x 10(-5) M) and compounds with shorter (methyl, butyl) aliphatic side-chains were inactive whilst activity increased dramatically in those compounds with octyl side-chains. Lipophilicity and calculated molecular volumes correlated linearly and bulkier, more lipophilic molecules had increasing activities in the electrophysiological assay. We therefore conclude that bulky substituents on the nitrogen atom increase calcium antagonistic activity in this series of compounds.

Animals↗

Characterization of dioxin-like activity of sediments from a Czech river basin.

Synthetic organic chemicals are present in environmental compartments as complex mixtures and therefore their potential effects are difficult to predict. In this study, in vitro bioassays using wild-type fish and rat hepatoma cell lines and their corresponding recombinant cell systems were used to evaluate 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like activity in extracts of sediments collected from rivers of the Czech Republic. All the sediment extracts elicited statistically significant responses in all the cell lines tested. For most sediment extracts, a complete dose-response relationship was obtained. The maximal efficacy of the samples was between 57 and 143% of the maximal induction elicited by TCDD. Greater responsiveness, sensitivity, and reproducibility were observed for recombinant than wild-type cells. Cell line-specific differences in the sensitivity to compounds present in the complex sediment extracts were observed. The TCDD equivalents (TCDD-EQs) determined from the different cell bioassays were correlated. Greater concentrations of TCDD-EQs were obtained with fish cell lines. The TCDD-EQs calculated from the results of chemical analysis of toxic equivalents (TEQs) were in good agreement with those determined by bioassays; the arly hydrocaron receptor (AhR)-effects of the identified chemicals appear to be generally additive. This indicates that most of the TCDD-like activity was accounted for by the compounds identified and quantified by instrumental analysis. Fractionation along with mass-balance calculations allowed identification of the active fractions and classes of compounds. Polycyclic aromatic hydrocarbons (PAHs) were found to be responsible for most of the AhR-mediated activity in sediments.

Animals↗

[Selectivity tuning in multi-binary eluents for reversed-phase liquid chromatography (RPLC)].

In this article, the retention equation and the relationship between retention parameters and the parameters of molecular structure deduced from statistical thermodynamics in RPLC have been used to explain the difference of selectivity towards a particular species of compounds polycyclic aromatic hydrocarbons (PAHs). Methanol/water, acetonitrile/water and isopropanol/acetonitrile have been provided in advance, then the retention behaviors of sixteen PAHs under three binary solvent systems have been investigated. It is found that each pair of binary solvents of methanol/water, acetonitrile/water and isopropanol/acetonitrile has its own unique selectivity. The best selectivity obtained for acenaphthene and fluorene is methanol/water system for fluoranthene and pyrene is acetonitrile/water, and for benzo[g,h,i]perylene and dibenzo[a,h]anthracene is isopropanol/acetonitrile. So a three-stepwise gradient elution of multi-binary mobile phase can be chosen for separation of 16 PAHs.

Acenaphthenes↗

A preliminary study of the changes in the direct-acting mutagenicities of several nitropolycyclic aromatic hydrocarbons after exposure under sunlight.

Five commercially available nitropolyclyclic aromatic hydrocarbons (nitro-PAH), namely, 4-nitrobiphenyl, 2-nitrofluorene, 9-nitroanthracene, 1-nitropyrene, and 2,7-dinitrofluorene, were exposed under restricted sunlight in the open air. The direct-acting mutagenicities of the samples after an exposure of 45 days were measured in order to compare them with those of the original samples in the Ames Salmonella typhimurium bioassay. It was found that the mutagenicities of some nitro-PAH do not change significantly while the mutagenicities of others increase or decrease after exposure. A preliminary study of nitro-PAH reaction products after exposure using GC, GC/MS, and FT-IR is also reported.

Anthracenes↗

[Changes in the larynx of rats induced by chemical carcinogens].

Carcinogenesis of the larynx induced by local application of 0.5% DMBA acetone solution or 1% methylnitrosourea acetone solution twice a week for 5-6 months was studied in 40 rats. The rats were killed by means of ether inhalation 7-12 months later. The carcinogens have induced epithelial hyperplasia, squamous cell metaplasia, acanthosis, dyskeratosis and hyperkeratosis, Epithelial downgrowths and papillomas have developed in 60-80% of animals. DMBA proved to be a stronger carcinogenic agent.

9,10-Dimethyl-1,2-benzanthracene↗

[Environmental carcinogens: mechanisms of action and occurrence. Some aspects (author's transl)].

New aspects on the mechanism of action of known environmental carcinogens are described. These compounds are not active as such, but are bioactivated in the mammalian metabolism via chemically reactive intermediates to electrophilic reactants, forming with information-bearing biopolymeres covalent bonds. This change in the genetic code is in agreement with the mutation hypothesis of carcinogenesis. Aflatoxin B1, N-nitroso compounds and benzo(a)pyrene are taken as examples. "Threshold levels", e.g. no-effect-levels derived from animal experiments with all their inherent limitations, are compared with data from human exposure to benzo(a)pyren, aflatoxine, N-nitroso compounds and vinyl chloride. The difficulties of such risk evaluations are discussed.

Aflatoxins↗

Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens.

The induction of resistant hepatocytes in vivo in the rat has been observed with 21 different chemical carcinogens. The resistance was measured by the ability of the cells to proliferate as focal lesions in the presence of an environment that inhibits the original or surrounding hepatocytes from proliferation. This was created by a dietary 2-acetylaminofluorene plus a stimulus for cell proliferation, a single necrogenic dose of CCl4. The foci were readily visualized by staining for gamma-glutamyl transpeptidase activity. With most of the chemicals, a single administration at an appropriate time after partial hepatectomy is efficacious. However, with safrole and dieldrin, three doses over a 36-hr period were required to induce a significant number of foci of resistant hepatocytes. The presumptive preneoplastic nature of the resistant hepatocytes and the possible usefulness of this approach for the development of a new in vivo short-term test system for carcinogens are discussed.

2-Acetylaminofluorene↗

Reduction of benzo(a)pyrene induced chromosomal aberrations by DL-alpha-tocopherol.

The antioxidant, DL-alpha-tocopherol (vitamin E), has been demonstrated to significantly reduce the percentage of benzo(a)pyrene (BP) induced chromosomal aberrations in vitro. Chinese hamster lung (Don) and Chinese hamster ovary (CHO) cells were treated with either 1 microgram/ml or 5 micrograms/ml BP for 4 to 28 h; some cultures were treated with S9 mix activated BP. Additional cultures of Don and CHO were treated simultaneously with 100 micrograms/ml of DL-alpha-tocopherol and BP. In CHO cells 1 microgram/ml non-activated BP significantly increased the chromosomal aberration percentage above the control level. Aberrations observed included breaks, gaps, fusions, rings, dicentrics, and polyploids. Chinese hamster Don cells treated with 1 microgram/ml or 5 micrograms/ml S9 mix activated BP contained significant increases in aberration percentages above the control levels. When Don cells were treated simultaneously with activated BP and DL-alpha-tocopherol for 4 h, there was a slight decrease in the total aberration frequency to less than that of cells treated with activated BP only; however, when Don cells were treated with BP and DL-alpha-tocopherol for 28 h, there was a significant reduction in the aberration percentage below that of BP-treated cells alone. Similar results have been obtained with CHO cells treated with nonactivated BP and DL-alpha-tocopherol. The results reported here provide further evidence that antioxidants may prevent the potential mutagenic and carcinogenic effects of certain polycyclic compounds.

Animals↗

Tumours in mice after subcutaneous injection of automobile exhaust condensates.

Automobile exhaust condensate (AEC), either mixed with benzo[a]pyrene (BaP) or suspended or dissolved in tricaprylin, was injected subcutaneously into NMRI mice in a series of experiments. The addition of AEC decreased the incidence of tumours which developed with 30, 90 and 270 microgram BaP. Reduction of tumour incidence was proportional to the amount of AEC added. With an injection of 10 microgram BaP, the latent period was greatly increased when AEC was added, but the occurrence of tumours was the same. Components of AEC appear to inactivate BaP, at least temporarily. In further experiments AEC and nine fractions thereof were injected subcutaneously into mice. The fraction comprising only polycyclic aromatic hydrocarbons (PAH) induced the highest incidence of tumours. In contrast, when it was administered in combination with other fractions the PAH fraction was less active. Application of the products of further fractionation of PAH showed that polycyclic compounds with seven or more rings can also induce tumours in this model.

Animals↗