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PubMed1985

Effect of aryl hydrocarbon hydroxylase induction on the in vivo covalent binding of 1-nitropyrene, benzo[a]pyrene, 2-aminoanthracene, and phenanthridone to mouse lung deoxyribonucleic acid.

The effect of aryl hydrocarbon hydroxylase induction on the covalent binding of 1-nitropyrene (1-NP), benzo[a]pyrene (BaP), 2-aminoanthracene (2-AA), and phenanthridone (PNDO) to mouse lung DNA was investigated. Cytochrome P-450-dependent monooxygenases were induced in mouse lung by intratracheal instillation of BaP, Aroclor-1254, or coal gas condensate (CGC) 24 hr before instillation of [3H]BaP, [3H]-2-AA, [14C]-1-NP, or [14C]PNDO. All inducing agents increased the amount of radioactivity of [3H]BaP, [3H]-2-AA, and [14C]-1-NP or metabolites bound to DNA. However, pretreatment with BaP resulted in the highest amounts of radiolabels covalently bound to DNA. At 4 hr after instillation of radiolabels in BaP-induced mice, the amounts of [3H]BaP, [3H]-2-AA, and [14C]-1-NP bound to DNA were increased 5.4-, 5.2-, and 160-fold above that of control levels; the amount of 1-NP bound to DNA was fifty times higher than the amount bound by BaP. Labeled compounds were still bound to DNA 1 week after administration. [14C]PNDO was not bound to DNA in uninduced or induced mice. Based on the amount of labeled compounds bound to DNA, pretreatment of mice with BaP and CGC induced enzymes with similar specificities; however, enzymes induced by Aroclor were less effective in the metabolism of labeled compounds to DNA-bound products. These data show that specific cytochrome P-450-dependent monooxygenases are inducible in mouse lung and suggest that pre-exposure to inducing agents may be important in the potential toxicity to proximal tissues in direct contact with inhaled xenobiotics.

Animals↗
PubMed2006

Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: potential scaffolds for peptide mimetics.

The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to alpha- or beta-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.

Aldehydes↗
PubMed1996

Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors.

Tetrahydroanthracene, tetrahydrophenanthrene, and tetrahydrophenalene moieties were used to design novel constrained melatoninergic agents. Compounds 1 and 2 were synthesized from the cyclization of the aryl succinic acids 6a,b followed by catalytic reduction, Curtius degradation to the amino derivatives, and acetylation. The phenalene derivatives 3 were prepared by cyclization of the aza lactones of the corresponding alpha-N-acetyl amino acids. The ketone derivatives were reduced directly by catalytic hydrogenation to produce the compounds 3. The different compounds were evaluated in vitro in binding assays using 2-[125I] iodomelatonin and chicken brain membranes. Melatonin and 2-acetamido-8-methoxytetralin were used as the reference compounds. The results showed the superiority of the dihydrophenalene framework 3 over those of tetrahydroanthracene and tetrahydrophenanthrene. 3a had relatively good affinity for melatonin receptors (Ki = 28.7 nM). Introduction of an additional methoxy group gave a derivative (3c) with nanomolar affinity (Ki = 0.7 nM), confirming the existence of a secondary binding site in the receptor which has been described previously. An increase in the affinity was also observed with the propionamido derivative 3e (Ki = 6.0 nM). The potential agonist properties of the compound 3e were evaluated on the dermal melanocytes of Xenopus laevis tadpoles. At the concentration of 2.3 nM (5 x Ki), melatonin gave a melanophore index value of 1. Similarly to melatonin, 3e was shown to be a potent agonist of the melanosome aggregation.

Amides↗
PubMed1977

Tumur induction by 7H-dibenzol[c,g] carbazole in the respiratory tract of Syrian hamsters.

The respiratory tract of male and female Syrian golden hamsters was treated intratracheally with 7H-dibenzo[c,g]carbazole (DBC), a tobacco smoke component. The carcinogen was given by multiple instillations at two dose levels. At the lower dose (9 mg), 35 of 46 hamsters (72%) developed respiratory tract tumors. The group receiving treatment at the higher dose level (30 mg) died earlier because of the toxicity of the compound. In this group, 15 of 45 animals (33%) had respiratory tract tumors. These occurred in the larynx, trachea, bronchi, and lungs, but predominated in the trachea and bronchi. Morphologically, most tumors were papillomas and squamous cell carcinomas. This study indicates the highly potent carcinogenic effect of DBC and that respiratory tumors can be induced in this model system without any carrier dust.

Animals↗
PubMed1993

Inhibition of smooth muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols.

alpha-Tocopherol, the most active form of vitamin E, causes a dose-dependent inhibition of serum-induced proliferation of smooth muscle cells (A7r5) in culture. Some tocopherol-related compounds exhibiting various degrees of antioxidant potency have also been tested on cellular proliferation. No direct correlation between the antioxidant activity of these compounds and their effect on smooth muscle cell growth could be observed. While most of the derivatives employed were not effective in inhibiting protein kinase C, in the case of alpha-tocopherol the antiproliferative effect was found to be parallel to the inhibition of protein kinase C activity, as measured in streptolysin-O permeabilized cells.

Alkaloids↗
PubMed1994

Antitumor agents. 7. Synthesis and antitumor activity of novel hexacyclic camptothecin analogues.

Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.

Animals↗
PubMed1979

Tumor initiating activity of 5,11-dimethylchrysene and the structural requirements favoring carcinogenicity of methylated polynuclear aromatic hydrocarbons.

The tumor initiating activities of 5,11-dimethylchrysene and 5-methylchrysene on mouse skin were compared. After initiating doses of 30 microgram or 10 microgram, with promotion by 3 times weekly applications of tetradecanoylphorbol acetate, both compounds were highly tumorigenic, inducing tumors in 70--85% of the treated animals. Since 5,12-dimethylchrysene had previously been shown to be only a weak tumor initiator, these results support the generalization that the structural requirements favoring carcinogenicity among the methylated chrysenes and other polynuclear aromatic hydrocarbons (PAH) are a bay region methyl group and a free peri position, both adjacent to an unsubstituted angular ring.

Animals↗
PubMed2003

Screening of novel pentacyclo-undecylamines for neuroprotective activity.

A novel series of pentacyclo-undecylamines with 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) as the lead compound was synthesised and screened for neuroprotective activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian mouse model. We hypothesise that these compounds may attenuate excitotoxic neuronal cell death mediated through the NMDA receptor (similar to memantine), and through calcium channel block. The pentacyclo-undecylamines (300 mg/kg) were administered to C57BL/6 mice 30 min before intraperitoneal (i.p.) MPTP administration (35 mg/kg). Striatal dopamine, 3,4-hydroxyphenylacetic acid (DOPAC), and homovanillic acid levels were analysed 10 days later by means of HPLC with electrochemical detection. Increased levels of DOPAC and homovanillic acid were observed when some of the test compounds were administered together with MPTP (compared to animals receiving only MPTP). One compound in the series, 8-phenylethylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane, attenuated MPTP-induced striatal dopamine depletion when compared to animals treated with MPTP only (p<0.05).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1975

Ultrasonic extraction of total particulate aromatic hydrocarbons (TpAH) from airborne particles at room temperature.

A superior enrichment procedure for the extraction of TpAH from airborne particles collected on glass fiber filter paper is described. The sample is suspended in a solvent and subjected to ultrasonic waves at room temperature with glass powder to adsorb polar coextractives. The TpAH in the filtered extracts are separated from other compounds by high speed liquid chromatography. Sensitivity is in the nanogram range, and the procedure is highly reproducible. Significantly larger amounts of TpAH are recovered than with Soxhlet extraction for 6 to 8 hours, and the percentage of pAH in the extracts is much higher. The entire procedure requires approximately 40 minutes, most of which is waiting time.

Air Pollutants↗
PubMed1995

Cycloclasticus pugetii gen. nov., sp. nov., an aromatic hydrocarbon-degrading bacterium from marine sediments.

Three heterotrophic bacterial strains were isolated from different locations in Puget Sound, Washington, by using biphenyl as the principal carbon source. These strains grow by using a limited number of organic compounds, including the aromatic hydrocarbons naphthalene, phenanthrene, anthracene, and toluene, as sole carbon sources. These aerobic, gram-negative rods are motile by means of single polar flagella. Their 16S rRNA sequences indicate that they are all members of the gamma subdivision of the Proteobacteria. Their closet known relatives are the genera Methylobacter and Methylomonas (genera of methane-oxidizing bacteria), uncultured sulfur-oxidizing symbionts found in marine invertebrates, and clone FL5 containing 16S ribosomal DNA amplified from an environmental source. However, the Puget Sound bacteria do not use methane or methanol as a carbon source and do not oxidize reduced sulfur compounds. Furthermore, a 16S rRNA base similarity comparison revealed that these bacteria are sufficiently different from other bacteria to justify establishment of a new genus. On the basis of the information summarized above, we describe a new genus and species, Cycloclasticus pugetti, for these bacteria; strain PS-1 is the type strain of C. pugetti.

Base Composition↗
PubMed2001

Influence of heavy organic pollutants of anthropic origin on PAH retention by kaolinite.

The adsorption of heavy fuel oil No. 2 (F2) on a reference kaolinite (Arvor kaolin, France), and the influence of this anthropic organic matter on the phenanthrene (PHEN) retention capacity of a kaolinite were investigated in the laboratory. The heaviest and most polar compounds of F2 are adsorbed on kaolinite preferentially to the other compounds and also partly irreversibly. The precoating of kaolinite by F2 significantly increases the sorption of PHEN in the range of concentrations studied (10-500 microg l(-1)). The partition coefficients normalized to organic carbon content (Koc) of kaolin precoated with fuel oil (5.2 < log Koc < 5.5) are one order of magnitude higher than those of the original kaolin (4.2 < logKoc < 4.5), and show very good agreement with the literature for polluted industrial soils. The Koc measured on the uncoated kaolin are in close agreement with the values determined for natural soils in which humic substances represent the organic component. This demonstrates that the composition of organic matter is the primary factor in PHEN retention by the soils. Therefore, in predicting the transport of PHEN, and other Polycyclic aromatic hydrocarbons (PAHs) in general, in soils of industrial sites containing heavy hydrocarbons or tars requires that the specific nature of the organic matter contained in these soils be taken into consideration.

Adsorption↗
PubMed1981

An E coli microsuspension assay for the detection of DNA damage induced by direct-acting agents and promutagens.

We have devised a microsuspension assay utilizing E coli indicator strains WP2, WP2 uvrA, WP67, CM611, WP100, W3110polA+, and p3478 pola- for the detection of chemically-induced preferential kill of repair-deficient strains. Data are presented from tests of 77 compounds representing a wide range of chemical classes which demonstrate the efficiency of the E coli microsuspension assay as both a qualitative and quantitative screen of DNA-modifying activity. Furthermore, the use of a battery of indicator strains lacking different repair systems offers the advantage of providing preliminary information concerning the mechanism of DNA damage induction by a test agent.

Alkylating Agents↗
PubMed1995

The exposure of cyclists, car drivers and pedestrians to traffic-related air pollutants.

Volunteers provided with personal air sampling (PAS) equipment covered concurrently, by car or bicycle, various selected routes. These comprised two inner city routes in Amsterdam (ICR 1 and 2) as well as a route including a tunnel on a busy highway (TR) and a rural route just south of Amsterdam (RR). A third inner city route, a busy narrow street, was subsequently also selected, and covered by bicycle or walking (ICR 3). Each run lasted about 1 h; the sampling time on the TR route was approximately 30 min. The sampling periods in January and May lasted 2 weeks with four sampling days per week. In August only ICR 3 was covered, this sampling period lasted 2 days. CO, NO2, benzene, toluene and xylenes were measured in the personal air samples. A monitoring vehicle covered the routes concurrently and measured CO, NO2 and pm10 (semi) continuously. Lead and PAH content in pm10 was determined. The ventilation of the volunteers was measured while they were using a car or a bicycle. The route and the type of transport influenced (P < 0.001) the concentrations of CO, benzene, toluene and xylenes. The daily average temperature was positively associated with the exposure of car drivers and cyclists to most compounds measured. A volunteer exhaled on average 2.3 times more air as a cyclist than as a car driver. Despite the much higher concentrations in the personal air samples of car drivers, the uptake of CO, benzene, toluene and xylenes of cyclists sometimes approached that of the car drivers. The uptake of NO2 of cyclists was clearly higher than that of car drivers.

Adult↗
PubMedDate not supplied

Identification of vimentin in rat peritoneal mast cells and its phosphorylation in association with histamine release.

Stimulation of rat peritoneal mast cells with histamine releasers, such as compound 48/80 and substance P, caused a similar pattern of protein phosphorylations: the molecular weights of the two major phosphorylated proteins were 45 kDa and 59 kDa. When rat mast cells permeabilized with beta-escin were exposed to Ca2+ at concentrations higher than 0.6 microM, phosphorylated proteins of identical molecular weight were also detected. By a radioimmunoprecipitation assay using anti-vimentin mouse monoclonal antibody, the 59 kDa protein was identified as vimentin, one of the intermediate cytoskeletal proteins. Moreover, it became apparent that the phosphoamino acid in phosphorylated vimentin was a serine residue. Sequential changes in vimentin phosphorylation were similar to that of histamine release elicited by histamine releasers: phosphorylation took place within 5 s of stimulation and reached a maximum within 10 s. When permeabilized mast cells were treated with calphostin C, a specific protein kinase C inhibitor, phosphorylation was markedly inhibited. Fluorescence images of mast cells stained with FITC-labelled anti-vimentin antibody showed filamentous structures surrounding the granules in the cytoplasm. However, after exposure to compound 48/80, the filamentous structures promptly disappeared and a dim fluorescence was observed homogeneously in the cell indicating that a rapid depolymerization of vimentin had taken place. From the present study, it became clear that when rat peritoneal mast cells were stimulated, vimentin was rapidly phosphorylated by protein kinase C and this phosphorylation process seems to be related to histamine release.

Animals↗
PubMed1998

Genotoxicity of coke-oven and urban air particulate matter in in vitro acellular assays coupled with 32P-postlabeling and HPLC analysis of DNA adducts.

This study is an in vitro part of the ongoing biomarker studies with population from a polluted region of Northern Bohemia and coke-oven workers from Czech and Slovak Republics. The aim of this study is to compare DNA adduct forming ability of chemical compound classes from both the urban and coke-oven extractable organic mass (EOM) of airborne particles. The crude extracts were fractionated into seven fractions by acid-base partitioning and silica gel column chromatography. In in vitro acellular assays we used calf thymus DNA (CT DNA) with oxidative (+S9) and reductive activation mediated by xanthine oxidase (+XO) under anaerobic conditions. Both the butanol and nuclease P1 versions of 32P-postlabeling for detection of bulky aromatic and/or hydrophobic adducts were used. The results showed that the spectra of major DNA adducts resulting from both the in vitro assays are within the fractions similar for both the urban and coke-oven samples. The highest DNA adduct levels with S9-activation were detected for the neutral aromatic fraction, followed by slightly polar and acidic fractions for both samples. With XO-mediated metabolism, the highest DNA adduct levels were detected for both the acidic fractions. Assuming additivity of compound activities, then the acidic fraction, which in the urban sample comprises a major portion of EOM mass (28%), may contain the greatest activity in both in vitro assays (39 and 69%, +S9 and +XO, respectively). In contrast, the aromatic fraction constituting only 8% of total urban EOM mass may account for comparable activity (34%) with organic acids. The highest DNA adduct forming activity of the coke-oven sample accounts for the aromatic fraction (82 and 63%, +S9 and +XO, respectively) that also contains the greatest portion of the total EOM (48%). To characterize some of the specific DNA adducts formed, we coupled TLC on 20x20 cm plates with HPLC analysis of 32P-postlabeled adducts. In both S9-treated samples of the aromatic fraction, we tentatively identified DNA adducts presumably diolepoxide-derived from: 9-hydroxy-benzo[a]pyrene (9-OH-B[a]P), benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide[+/-] (anti-BPDE), benzo[b,j,k]fluoranthenes (B[b]F, B[j]F, B[k]F), chrysene (CHRY), benz[a]-anthracene (B[a]A) and indeno[cd]pyrene (I[cd]P). These DNA adducts accounted for about 57% of total DNA adducts detected in both S9-treated samples of the aromatic fraction. DNA adducts of XO-treated samples were sensitive to nuclease P1 and HPLC profiles of the major adducts were markedly different from the major adducts of S9-treated samples. However, the combination of TLC and HPLC did not confirm the presence of DNA adducts derived from 1-nitropyrene (1 NP), 9-nitroanthracene (9 NA) and 3-nitrofluoranthene (3 NF) that were detected by GC-MS in the slightly polar fraction. We concluded that the chemical fractionation procedure facilitates the assessing of DNA adduct forming ability of different chemical compound classes. However, based on the results obtained with the whole extracts, it does not fulfil a task of the actual contribution of individual fractions within the activity of the whole extracts. Our results are the first in detecting of DNA adducts derived from urban air and coke-oven particulate matter.

Air Pollutants↗
PubMed1991

Cytochrome P-450 monooxygenase systems in aquatic species: carcinogen metabolism and biomarkers for carcinogen and pollutant exposure.

High levels of polynuclear aromatic hydrocarbon (PAH) carcinogens commonly occur in aquatic systems where neoplasms arise in fish and other animals. Enzymes that transform PAHs can act in initiating these diseases and can indicate the contamination of fish by carcinogens and other pollutants. Cytochrome P-450 has similar roles in activating PAH carcinogens in fish and mammalian species. PAHs and many chlorinated hydrocarbons, e.g., polychlorinated biphenyls (PCBs) induce a form of cytochrome P-450 in fish that is the primary catalyst of PAH metabolism. The induction of this P-450 in fish can accelerate the disposition of hydrocarbons, but can also enhance the formation of carcinogenic derivatives of PAHs. Invertebrates have lower rates of PAH metabolism than fish. These rates are not obviously inducible by exposure to PAHs or PCBs. The lower rates of foreign compound metabolism contribute to higher pollutant residue levels in bivalve mollusks (clams, mussels, etc.) than in fish and may limit the involvement of some procarcinogens (requiring activation) in disease processes in invertebrates. The induction of P-450 forms can indicate the exposure of fish to PAHs, PCBs, and other toxic compounds. This is not restricted to carcinogens. Environmental induction has been detected in fish from contaminated areas by use of catalytic assay, antibodies to fish P-450, and cDNA probes that hybridize with P-450 messenger RNA. Application of these methods can provide sensitive biological monitoring tools that can detect environmental contamination of fish by some carcinogens and tumor promoters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[The comparative characteristics of the interferon-inducing capacity of 2 preparations related to aromatic hydrocarbons].

Aromatic hydrocarbons are rightly considered to belong to most active synthetic interferon inducers among low molecular compounds. A comparative evaluation of L-1 (acridanon) and amixin (fluorenon) showed L-1 to have more marked interferon-inducing properties. Both compounds differed not only in the dynamics and levels of interferon synthesis in different organs which suggests the possibility of their employment in different diseases, but also in the efficacy of the modes of application. L-1 induced IF synthesis most actively after subcutaneous inoculation, amixin after oral administration.

Acridines↗
PubMed1989

32P-postlabeling analysis of DNA adducts in liver of wild English sole (Parophrys vetulus) and winter flounder (Pseudopleuronectes americanus).

The 1-butanol adduct enhancement version of the 32P-postlabeling assay was used to measure the levels of hepatic DNA adducts in the marine flatfish, English sole (Parophrys vetulus), sampled from the Duwamish Waterway and Eagle Harbor, Puget Sound, WA, where they are exposed to high concentrations of sediment-associated chemical contaminants and exhibit an elevated prevalence of hepatic neoplasms. Hepatic DNA was also analyzed from English sole from a reference area (Useless Bay, WA) and from reference English sole treated with organic-solvent extracts of sediments from the two contaminated sites. Autoradiograms of thin-layer chromatograms of 32P-labeled hepatic DNA digests from English sole from the contaminated sites exhibited up to three diagonal radioactive zones, which were not present in autoradiograms of thin-layer chromatogram maps of 32P-labeled DNA digests from English sole from the reference site. These diagonal radioactive zones contained several distinct spots as well as what appeared to be multiple overlapping adduct spots. The levels (nmol of adducts/mol of nucleotides) of total DNA adducts for English sole from Duwamish Waterway and Eagle Harbor were 26 +/- 28 (DS) and 17 +/- 9.6, respectively. All autoradiograms of DNA from fish from the contaminated sites exhibited a diagonal radioactive zone where DNA adducts of chrysene, benzo(a)pyrene, and dibenz(a,h)anthracene, formed in vitro using English sole hepatic microsomes, were shown to chromatograph. English sole treated with extracts of the contaminated sediments had adduct profiles generally similar to those for English sole from the respective contaminated sites. The chromatographic characteristics of the adducts and the similarities in adduct profiles between field-sampled English sole and those treated with contaminated sediment extracts suggested that hydrophobic aromatic compounds of anthropogenic origin were adducted to hepatic DNA of sole from contaminated sites, but not in sole from the reference site. Moreover, an initial study with winter flounder (Pseudopleuronectes americanus) from Boston Harbor, MA, an area where high concentrations of sediment-associated chemicals are present, revealed a pattern of hepatic DNA-adducts (9.0 +/- 7.8 nmol of adducts/mol of nucleotides) similar to that observed for English sole from Eagle Harbor.

Animals↗