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PubMed1993

Identification of polycyclic aromatic hydrocarbons in mutagenic adsorbates to a copper-phthalocyanine derivative recovered from municipal river water.

A study was made to identify polycyclic aromatic hydrocarbons (PAHs) in the mutagenic adsorbate to blue cotton recovered from the water of the Katsura River which is a tributary of the Yodo River, a typical municipal river. As blue cotton bears a covalently bound copper-phthalocyanine derivative which can adsorb PAHs over 3 rings, PAHs in the adsorbate were separated into 4 fractions (I-IV) by Sephadex LH-20 gel chromatography. Fractions III and IV showed high direct and indirect frameshift mutagenicity in strains YG1021 and YG1024, the nitroreductase- and O-acetyltransferase-overproducing derivatives of TA98, especially in YG1024 with S9 mix, whereas these fractions showed less mutagenicity in TA98NR or TA98/1,8-DNP6. These results suggest that mutagenic nitroarenes and aminoarenes are present in both fractions. The retention times of some peaks separated from both fractions using high performance liquid chromatography (HPLC) with a fluorescence detector were identical with those of authentic PAHs. Gas chromatography-mass spectrometry of some HPLC fractions demonstrated that anthraquinone, azulene derivative, quinoline derivative, chrysene and benzo[b]fluoranthene are probably contained in these fractions.

Adsorption↗
PubMed1994

In vivo metabolism and genotoxic effects of nitrated polycyclic aromatic hydrocarbons.

During incomplete combustion of organic matter, nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), are formed in a reaction that is catalyzed by a low pH. 2-Nitrofluorene (NF), a marker for nitro-PAHs, is metabolized in vivo by two different routes. After inhalation, potent mutagenic metabolites, hydroxylated nitrofluorenes (OH-NFs), are formed. The metabolites are distributed by systemic circulation. After oral administration, NF is reduced to the corresponding amine, a reaction mediated by the intestinal microflora. This metabolite is acetylated to 2-acetylaminofluorene (AAF), a potent carcinogen. Further ring-hydroxylation of AAF leads to detoxification and excretion. Induction of cytochrome P450s affects the metabolism, and more OH-NFs are formed. As a consequence, more mutagenic metabolites are found in the circulation. OH-NFs are excreted in the bile as, in terms of mutagenicity, totally harmless glucuronide conjugates. When these conjugates are excreted via the bile, intestinal beta-glucuronidase can liberate direct-acting mutagens in the intestine. Thus, inhalation of NF can lead to formation of potent mutagens in the intestine. NF is a direct-acting mutagen in bacterial assays and an initiator and promoter of the carcinogenic process, and gives rise to DNA adduct formation in laboratory animals.

Administration, Inhalation↗
PubMed1985

The contribution of polycyclic aromatic hydrocarbon fractions with different boiling ranges to the carcinogenic impact of emission condensate from coal fired residential furnaces as evaluated by topical application to the skin of mice.

Flue gas condensate from briquet-fired residential furnaces was separated into a polycyclic aromatic compound (PAC)-free and a PAC-containing part, followed by a subfractionation of the PAC-containing fraction into 3 parts: PAC consisting predominantly of (a) 2 and 3 rings, (b) 4 and 5 rings and (c) 6 and more rings. To evaluate the carcinogenic potency of the condensate and its fractions, local application onto skin of mice in 2 or 3 doses was used. Since it was known from an earlier investigation that both the PAC-free fraction and the fraction containing PAC with 2 and 3 rings were almost ineffective, only PAC-fractions containing more than 3 rings were tested. The probit and Weibull analysis of the results showed that the condensate and the fractions containing PAC with 4 and 5 rings as well as 6 and more rings provoke local tumors after repeated application to the dorsal skin of mice. The tumor incidence exhibited a clear cut dose-response relationship. Fractions (b) and (c) were almost equally active, each contributing by about 50% to the total carcinogenicity. The content of benzo[a]pyrene (0.72 mg/g condensate) contributed by 10-11% to the total carcinogenicity of the emission.

Administration, Topical↗
PubMed1992

Transcriptional derepression of the murine Cyp1a-1 gene by mevinolin.

In mouse hepatoma Hepa-1c1c7 cultures, polycyclic aromatic compounds such as benzol[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) activate the Cyp1a-1 (cytochrome P(1)450) and Nmo-1[NAD(P)H:menadione-oxidoreductase] genes, two members of the aromatic hydrocarbon (Ah)-responsive gene battery. Mevinolin is known to inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (EC 1.1.1.34), the rate-limiting step in cholesterol biosynthesis. We show here that in the absence of TCDD, mevinolin markedly increases Cyp1a-1 transcription, CYP1A1 mRNA and protein levels and enzyme activity, and NMO1 mRNA concentrations. Addition of mevalonate, the product of HMG-CoA reductase activity, fails to reverse the effects of mevinolin. In fact, when used at high concentrations, mevalonate activates Cyp1a-1 transcription. Mevinolin-induced Cyp1a-1 gene activation: (1) occurs independently of the lipid content of the growth medium, (2) is not suppressed by adding 25-hydroxycholesterol, which blocks MHG-CoA reductase activity, and (3) requires a functional Ah receptor and unimpaired nuclear translocation of the receptor. It is possible that an unknown metabolite (or metabolites) of mevinolin activates Cyp1a-1 expression and that high concentrations of mevalonate act via the same mechanism. Using chimaeric plasmids that contain different lengths of Cyp1a-1 5' flanking regions fused to the bacterial neomycin (neo) gene, we find that the mevinolin effect on Cyp1a-1 induction requires the 5' flanking sequences between -1647 and -824, which are also needed for TCDD induction. Mevinolin, however, is not a ligand for the Ah receptor. Gel mobility shift assays revealed that Cyp1a-1 activation caused by mevinolin does not involve the ligand-dependent formation of a functional Ah receptor-dependent DNA-binding complex, but instead appears to be correlated with release of a putative repressor from its cognate DNA site. Our results suggest that the basel level of Cyp1a-1 transcription is maintained by an unknown negative regulatory factor. We propose that Cyp1a-1 transcriptional activation can result not only from induction by polycyclic aromatic compounds but also from derepression by mevinolin, independent of HMG-CoA reductase inhibition.

Animals↗
PubMed1993

Comparison of DNA adducts from exposure to complex mixtures in various human tissues and experimental systems.

DNA adducts derived from complex mixtures of polycyclic aromatic compounds emitted from tobacco smoke are compared to industrial pollution sources (e.g., coke ovens and aluminum smelters), smoky coal burning, and urban air pollution. Exposures to coke oven emissions and smoky coal, both potent rodent skin tumor initiators and lung carcinogens in humans, result in high levels of DNA adducts compared to tobacco smoke in the in vitro calf thymus DNA model system, in cultured lymphocytes, and in the mouse skin assay. Using tobacco smoke as a model in human studies, we have compared relative DNA adduct levels detected in blood lymphocytes, placental tissue, bronchoalveolar lung lavage cells, sperm, and autopsy tissues of smokers and nonsmokers. Adduct levels in DNA isolated from smokers were highest in human heart and lung tissue with smaller but detectable differences in placental tissue and lung lavage cells. Comparison of the DNA adduct levels resulting from human exposure to different complex mixtures shows that emissions from coke ovens, aluminum smelters, and smoky coal result in higher DNA adduct levels than tobacco smoke exposure. These studies suggest that humans exposed to complex combustion mixtures will have higher DNA adduct levels in target cells (e.g., lung) as compared to nontarget cells (e.g., lymphocytes) and that the adduct levels will be dependent on the genotoxic and DNA adduct-forming potency of the mixture.

Adult↗
PubMed1993

Nitrated polycyclic aromatic hydrocarbons: a risk assessment for the urban citizen.

Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) are formed during incomplete combustion. Sources include emissions from vehicles (mainly diesel vehicles), heating, smoking, certain types of food processing, and incomplete combustion in general. Nitro-PAHs are direct-acting mutagens, and a number of them have been shown to be carcinogens. 2-Nitrofluorene (NF) represents a model substance for the nitro-PAHs. An attempt has been made to calculate the human cancer risk due to exposure to nitro-PAHs by two different models. In the first model, genotoxic lesions were transferred to units of Gray (gamma-irradiation), and in the second model a mega study (24,000 animals) on the carcinogenicity of one metabolite of NF was used to elucidate the risk. Gamma-irradiation of the rat liver gave rise to preneoplastic foci in a dose-dependent manner, which was statistically significant. The Gray-equivalents of chemically (NF) induced foci were calculated, and from the human nitro-PAH exposure, expressed in Sievert, a human risk estimate was calculated. In the second model, an extrapolation from laboratory animals to man was performed because tumor data on 2-acetylaminofluorene (AAF), a major metabolite of NF, were available in the literature. The tumor dose-response data on AAF was linear for tested lifetime doses. The results of both models agreed, with a risk range of 0.15-49 x 10(-6) on human cancer risk for an urban citizen.

Animals↗
PubMed1989

Transient superinducibility of cytochrome P450c (CYP1A1) mRNA and transcription.

Simultaneous treatment of the rat hepatocyte-derived cell line LCS7 with cycloheximide and polycyclic aromatic compounds increased CYP1A1 (cytochrome P450c) gene transcription rate four- to sixfold and mRNA levels 20-fold relative to the levels in cells treated with inducers alone. When cycloheximide was added up to 1 hr after inducer, a similar degree of superinduction occurred. However, if cycloheximide was added at 1.5 hr or later, superinduction did not occur, even though an increased transcription rate continued at these times in cells treated with inducers alone. Thus, treatment with cycloheximide revealed two phases to the response of the CYP1A1 gene to inducer. During the early phase, inhibition of protein synthesis could amplify the effect of inducer. During the later phase, transcription rate and CYP1A1 mRNA levels remained elevated due to inducer treatment, but could not be further elevated by inhibiting protein synthesis. The superinduction of CYP1A1 mRNA was also examined in primary hepatocyte cultures and in explant cultures of three tissues. These varied substantially in their superinduction response. All of these exhibited elevated levels of CYP1A1 mRNA following simultaneous treatment with inducer and cycloheximide; transcription rate was superinduced three- to fourfold in primary hepatocytes, and CYP1A1 mRNA levels were superinduced 20- to 25-fold in both kidney and lung explants. However, the delayed addition of cycloheximide had varying effects in different culture systems. In primary hepatocytes, addition of cycloheximide as long as 4 hr after addition of inducer resulted in superinduction equal to that which occurred when these agents were added together. In contrast, adding cycloheximide only 2.5 hr after adding inducer resulted in undetectable superinduction in kidney explants and diminished superinduction 70% in lung explants. Although the time course of cycloheximide responsiveness following inducer treatment has been studied in detail only in LCS7 cells, it appears that the length of the cycloheximide-responsive phase is different in different cell culture systems in in explants from different tissues. This may be related to the previously reported tissue-specific differences in CYP1A1 gene expression.

Animals↗
PubMed1996

Developmental toxicity of clarified slurry oil, syntower bottoms, and distillate aromatic extract administered as a single oral dose to pregnant rats.

Clarified slurry oil (CSO), syntower bottoms (STB), and distillate aromatic extract (DAE) are refinery streams produced by processing crude oil. Each of these refinery streams is rich in both hydrocarbons having carbon numbers of C20 or greater and polycyclic aromatic compounds. Available data indicate that some refinery streams are developmentally toxic (manifested primarily as increased embryolethality and growth retardation) by the dermal route of exposure. However, there is no conclusive evidence for their being teratogenic. The present studies were designed to further explore the suspected teratogenic potency of refinery streams while at the same time limiting embryolethality. To profile teratogenic effects as a function of gestation day, pregnant rats received a single oral dose (2000 mg/kg) of CSO, STB, or DAE on one of gestation days (GD) 11-14; DAE and STB were also administered on GD 15. To profile effects as a dose response function, rats received a single oral dose of CSO, DAE, or STB on GD 12 at 125, 500, and 2000 mg/kg. Control animals were similarly treated but were administered tap water. On GD 20, dams were necropsied and the fetuses evaluated for normal development. In general, evidence of maternal toxicity (i.e., decreased body weight gain, decreased thymus weight) was observed at doses greater than or equal to 500 mg/kg. For each refinery stream tested, the incidence of resorption was greatest on GD 11. A common pattern of fetal malformations was observed for all of the refinery streams tested and included cleft palate, diaphragmatic hernia, and paw and tail defects. The incidence and type of malformation observed were influenced by the gestation day of exposure. The incidences of external and skeletal malformations were greatest on GD 11 and 12 for fetuses exposed to CSO; on GD 13 and 14, the incidence of malformation was comparable for CSO- and STB-exposed fetuses. The incidence of visceral anomalies was greatest on GD 11-13 for fetuses exposed to CSO and STB; on Gestation D 14, the incidence was comparable for each of the refinery streams tested. In general, the ability to produce adverse effects on development was greatest for CSO and least for DAE. Effects produced by STB were comparable to or less severe than those observed for CSO.

Abnormalities, Drug-Induced↗
PubMed1989

Nucleophilic selectivity of carcinogens as a determinant of enhanced mutational response in excision repair-defective strains in Drosophila: effects of 30 carcinogens.

Consequences on mutation induction of a defective excision repair (exr-) system have been studied in Drosophila for a series of 30 carcinogens, representing 17 mono-, six bi- or trifunctional agents, five cyclic alkylating agents and two polycyclic aromatic compounds. Repair-inactive spermatozoa or (late) spermatids were mutagenized and then transferred to excision-defective (mei-9L1) or appropriate excision proficient (exr+) oocytes. Hypermutability responses in exr- in relation to the exr+ genotype were determined by calculating frep-/frep- (ratio = y) indices at x = 1% X-linked recessive lethal mutations (SLRL); frep- denotes induced SLRL frequency in mei-9L1, frep+ that induced in repair-proficient condition, and x = 1 means 1% SLRL in exr+, A linear positive relationship between frep-/frep+ estimates and nucleophilic selectivity (Swain and Scott's constants s) was established for 18 carcinogens, representing either mono- and cyclic alkylating agents: frep-/frep+ = 12.4s - 1.9; r = 0.79, r2 = 0.62, P less than 0.01 Noticeable exceptions to this linear correlation indicated that, although nucleophilicity is a principle determinator for hypermutability response in exr- mutants, other cellular factors play a significant role as well. These are (i) the faster rate of removal of methyl adducts compared to ethyl derivatives, (ii) the complex metabolism of some of the carcinogens (PC, DTIC, DMPT, Cl3DMPT) and (iii) the length of the time period between DNA modification and onset of replication after fertilization. By contrast, CEO and polyfunctional agents (FA, HMPA, MC, MCT, Thio-TEPA and BCNU) did not follow the linear relationship. They provided lower frep-/frep+ indices than would be anticipated on the basis of their nucleophilic selectivity (MC, BCNU, Thio-TEPA) or were even inactive (FA, MCT, HMPA) in the Drosophila repair assay. Both in terms of consistency (mono- and cyclic alkylating agents) and exceptional behavior (CEO, the six crosslinking agents), there is an intriguing positive correlation between relative efficiency ranking of carcinogens and with respect to their position on the potency scale for hypermutability. Thus, in genetic terms, as most potent carcinogens in rodents appear to be those agents giving no effect or a low activity in the exr- genotype in Drosophila: carcinogens with high potential for direct miscoding [ENU, ENNG, DEN, iPMS, CEO and presumably DMBA (?)], and those capable of forming crosslinks (MC, MCT, HMPA, Thio-TEPA and BCNU).

Alkylating Agents↗
PubMed1991

Fluorescent markers for hypoxic cells. A study of novel heterocyclic compounds that undergo bio-reductive binding.

The bioreductive metabolism and binding of nitroaromatic compounds has been suggested as a method for the identification of hypoxic tumour cells. Bound metabolites of suitable nitroaryl compounds (and some other reducible aromatic compounds) may fluoresce, offering an alternative to radiolabelling or NMR etc. as a diagnostic method. In this paper, the synthesis of some heteroaromatic nitro-compounds is given together with the results obtained from testing of these and other mainly nitroaromatic compounds in vitro as potential bioreductive fluorescent probes for hypoxic cells in tumours. Compounds were incubated with oxygenated or hypoxic mammalian cell suspensions for various times before evaluation of the cellular fluorescence from bioreductive metabolites by fluorescence microscopy and flow cytometry. Among those compounds yielding fluorescent metabolites in cells, considerable variation in hypoxic:oxic differential fluorescence was observed. The in vitro mammalian cell test system showed several of the compounds to be sufficiently promising to merit further investigation in vivo.

Animals↗
PubMed2004

The distribution and relative toxic potential of organic chemicals in a PCB contaminated bay.

For reliable monitoring of environmental improvement, the PCB contaminated bay Orserumsviken on Sweden's Baltic coast was investigated prior to remediation. We examined PCB congener patterns and the relative toxic potential of PCBs in extracts of three matrices: bottom sediment, settling particulate matter and the dissolved phase (obtained from semi-permeable membrane devices). Congener patterns were similar in all matrices. Three fractions were isolated from the extracts: (1) aliphatic and monocyclic aromatic compounds (MAC-fraction), (2) dicyclic aromatic compounds (DAC-fraction), including PCBs, and (3) polycyclic aromatic compounds (PAC-fraction), including PAHs. Total extracts and fractions were injected into newly fertilised rainbow trout eggs. At larval stage, hepatic EROD activities were quantified. Though high, the PCB contamination could explain only an estimated 1-5% of the total EROD induction. The order of EROD induction potential was: total extract > PAC-fraction > DAC-fraction > MAC-fraction in all matrices, suggesting that in Orserumsviken PACs made a larger contribution to the EROD induction potential than PCBs and other DACs.

Animals↗
PubMed2000

Triribbed-functionalized clathrochelate iron(II) dioximates as a new and promising tool to obtain polynucleating and polynuclear compounds with improved properties.

Template condensation on iron(II) ion of dichloroglyoxime (H2C12Gm) with (C6H5O)3, n-C4H9B(O-n-C4H9)2, and BF3.O(C2H5)2 in CH3NO2 afforded reactive clathrochelate precursors Fe(C12Gm)3(BC6H5)2 (2), Fe(C12Gm)3(B-n-C4H9)2 (3), and Fe(C12Gm)3(BF)2 (4). A series of triribbed-functionalized clathrochelate dioximates have been synthesized. Reaction of 2 with C6H5SH/K2CO3 and CH3SH/t-C4H9OK in 1,4-dioxane and THF afforded Fe((C6H5S)2Gm)3(BC6H5)2 (5) and Fe((CH3S)2Gm)3(BC6H5)2 (6). Reaction of 3 with C6H5OK in THF afforded Fe((C6H5O)2Gm)3(B-n-C4H9)2 (7). Condensation of 3 with bis(2-(o-oxyphenoxy))diethyl ether in THF afforded di- and tricrown etheric Fe(CwGm)2(C12Gm)(Bn-C4H9)2 (8) and Fe(CwGm)3(B-n-C4H9)2 (9) clathrochelates. Condensation of 3 with 3,5-dithiaoctane-1,8-dithiol/Cs2CO3 in DMF afforded the thiocrown etheric Fe((12anS4)Gm)3(BC6H5)2 complex (10). Reaction of 2 with n-butylamine in DMF resulted in the tetrasubstituted Fe((n-C4H9NH)2Gm)2(C12Gm)(BC6H5)2 clathrochelate (11). The clathrochelates obtained have been characterized both on the basis of elemental analysis, FAB and PD mass spectrometry, IR, UV-vis, 57Fe Mössbauer, and NMR spectroscopies and crystallographically (compounds 3, 4, 6, 7, and 11). An encapsulated iron(II) ion in a distorted trigonal-prismatic environment of six nitrogen atoms of the macrobicyclic ligand was found to be in a low-spin state. The cyclic voltammograms for the complexes 2-11 show irreversible oxidation waves assignable to Fe3+/Fe2+ couples. The correlation of E1/2 for these couples with Hammet sigma para constants for substituents in dioximate fragments has been demonstrated.

Biocompatible Materials↗
PubMed2005

Allenyl azide cycloaddition chemistry. synthesis of pyrrolidine-containing bicycles and tricycles via the possible intermediacy of azatrimethylenemethane species.

Thermolysis of 5-azidoallenes bearing a C(1) methyl group and either an aryl ring or an alkene on C(1) furnishes tricyclic (from the aryl substrates) or bicyclic (from the alkenyl substrates) pyrrolidine products following formal H-CN addition across an intermediate imine. High levels of diastereoselectivity are observed in all cases studied. This reaction cascade presumably passes through unobserved triazoline and azatrimethylenemethane diyl intermediates en route to product.

Alkadienes↗