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PubMed2005

Halogenated thymidine analogues restore the expression of silenced genes without demethylation.

Transcriptional silencing of tumor suppressor genes by aberrant DNA methylation is a characteristic frequently observed in cancer cells. Therefore, reversing this process is a therapeutic target against cancer. In this study, we established a screening system for silencing inhibitors with cell lines transfected by a retroviral vector containing a luciferase gene. More than 100 nucleosides were tested for antisilencing activity with a selected clone in which the silenced expression of luciferase could be recovered by 5-aza-2'-deoxycytidine. A group of halogenated thymidine analogues was found to reactivate transcription of not only the reporter retrovirus vector but also endogenous glutathione-S-transferase 1 gene, without influence to DNA hypermethylation. Gel mobility shift assay showed that 5-bromo-2'-deoxyuridine (BrdUrd) or 5-iodo-2'-deoxyuridine incorporation did not affect the binding of the methyl-CpG binding protein motif to methylated DNA. Finally, in the retroviral promoter, BrdUrd treatment increased the acetylated histone H3 level and decreased methylation of histone H3 Lys9 in accordance with recovered transcription. This study shows that halogenated thymidines have an antisilencing effect without changing DNA methylation status by interfering with step(s) between DNA methylation and histone acetylation.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Cytosolic C-S lyase activity in human kidney samples-relevance for the nephrotoxicity of halogenated alkenes in man.

Human renal cortex cytosolic samples were screened for C-S lyase (EC 4.4.1.13) activity using cysteine conjugates of halogenated aliphatic and aromatic hydrocarbons as substrates. Cystosolic activity was greatest with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC) (72.0 +/- 26.8 and 74.4 +/- 38.3 nmol pyruvate formed/mg protein/120 min. respectively). Less than five fold inter-individual variation was observed. In contrast to the low C-S lyase activity detectable in rat cytosol, no cleavage of the aromatic conjugates S-(2-benzothiazolyl)-L-cysteine (BTC), S-(2,3,5,6-tetrachlorophenyl)-L-cysteine (TCPC) and S-(4-bromophenyl)-L-cysteine (4-BPC) was detectable in human cytosol. Structure-activity relationships showed that increasing the fluorinated carbon chain length of the halogenated hydrocarbon species decreased conjugate cleavage by C-S lyase. The position and number of fluorine and chlorine atoms on the parent hydrocarbon determined the extent of cysteine conjugate C-S cleavage. Activity increased with an increase in fluorine and chlorine substitution and shortening of carbon chain length in the rat, although in human cytosol an increase in chlorine substitution resulted in decreased activity.

Alkenes↗

PubMed2000

Structure-activity relationships for the Ca2+-releasing activity of 6-hydroxy-beta-carboline analogues in skeletal muscle sarcoplasmic reticulum-the effects of halogen substitution at C-5 and C-7.

This study of structure-activity relationships of 6-hydroxy-beta-carboline analogues has been performed on the basis of quantitative measurement of Ca2+-releasing activity in the sarcoplasmic reticulum of skinned fibres of skeletal muscle. Substitution of halogens for hydrogens at the C-5 and C-7 positions and further introduction of a methyl group into the N-9 position of 6-hydroxy-beta-carboline resulted in Ca2+-releasing activity. The 50% effective concentrations of 5,7-dibromoeudistomin D, 5,7-dichloroeudistomin D, 5,7-diiodoeudistomin D, 9-methyl-5,7-dibromoeudistomin D, 9-methyl-5,7-dichloroeudistomin D, 9-methyl-5,7-diiodoeudistomin D, and caffeine were 5.6 x 10(-6), 6.3 x 10(-6), 7.8 x 10(-6), 2.1 x 10(-6), 2.0 x 10(-5), 3.7 x 10(-5), and 4.7 x 10(-4) M, respectively, indicating that these analogues are 10-200 times more potent than caffeine. Substitution of bromine by chlorine or iodine at the C-5 and C-7 positions markedly reduced the activity of the analogues with a methyl group at the N-9 position. These results suggest that halogens at the C-5 and C-7 positions in the beta-carboline skeleton are essential for Ca2+-releasing activity and that an N-9 methyl group also affects the activity of these analogues. Thus, these 6-hydroxy-beta-carboline analogues might become powerful tools for studying the molecular mechanism of Ca2+ release in the sarcoplasmic reticulum.

Animals↗

PubMed2006

Determinants of volatile general anesthetic potency: a preliminary three-dimensional pharmacophore for halogenated anesthetics.

We investigated the molecular basis for the immobilizing activity of halogenated volatile anesthetics using comparative molecular field analysis. In vivo potency data (expressed as minimum alveolar concentrations) for 69 structurally diverse anesthetics were obtained from the literature. The drugs were randomly divided into a training set (n = 52) used to derive the activity model and a test set (n = 17) used to independently assess the model's predictive power. The anesthetic structures were aligned so as to maximize their similarity in molecular shape and electrostatic potential to the most potent drug in the group, CF2H-(CF2)3-CH2OH. The conformers and alignments of the anesthetics with maximum similarity (calculated as Carbo indices) were retained and used to derive the comparative molecular field analysis models. The final model explained 94.2% of the variance in the observed activities of the training set compounds. The model showed good predictive capability for both the training set (cross-validated r2 = 0.705) and randomly excluded test set anesthetics (r2 = 0.837). Three-dimensional pharmacophoric maps were derived to identify the spatial distribution of key areas where steric and electrostatic interactions are important in determining immobilizing activity of the halogenated drugs and were compared with our previously published maps obtained for nonhalogenated volatile anesthetics.

Anesthetics, General↗

PubMed2003

Activation of the human Ah receptor by aza-polycyclic aromatic hydrocarbons and their halogenated derivatives.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor through which dioxins and carcinogenic polycyclic aromatic hydrocarbons cause altered gene expression and toxicity. Ten aza-polycyclic aromatic hydrocarbons (aza-PAHs), consisting of nitrogen substituted naphthalenes, phenanthrenes, chrysenes, and benzo[a]pyrenes (BaPs), were subjected to analysis of their structure-activity relationships as an AhR ligand by using a yeast AhR signaling assay, in which AhR ligand activity was evaluated as lacZ units. Most of the aza-PAHs showed similar or more potent AhR ligand activities than the corresponding parent PAHs. About a 100-fold increased in ligand activity was observed in 10-azaBaP compared with BaP. Halogen-substitution effects on AhR ligand activity in aza-polycyclic aromatics were also investigated with quinoline, benzo[f]quinoline (BfQ), benzo[h]quinoline (BhQ) and 1,7-phenanthroline (1,7-Phe). Position-specific induction of AhR ligand activity was observed in aza-tricyclic aromatic compounds, BfQ, BhQ, and 1,7-Phe, and the ratio of the ligand activities (lacZ units/microM) of monochlorinated and monobrominated aza-tricyclic aromatic compounds to those of the corresponding parent non-halogenated compounds ranged from 2.2- to 254-fold. Greatest enhancement of ligand activity was observed in 2-brominated BfQ (2-Br-BfQ), and its ligand activity was higher than that of BaP. These results suggest that even monohalogenation markedly enhances AhR ligand activity in aza-PAHs.

Aza Compounds↗

PubMed1995

Synthesis and pharmacological effects in mice of halogenated cannabinol derivatives.

Eight halogenated derivatives of cannabinol (CBN) substituted on the aromatic ring at the 2 and/or 4 position were synthesized and their pharmacological effects were evaluated by intracerebroventricular injection (50 micrograms/mouse) in mice, using hypothermia, pentobarbital-induced sleep prolongation, catalepsy and anticonvulsant effect as indices. The hypothermic effects of monohalogenated derivatives of CBN were comparable to that of CBN, whereas the effects of dihalogenated derivatives of CBN except for the fluorinated derivative were attenuated. In the interaction with pentobarbital, two monochlorinated derivatives exhibited a significant prolongation of sleeping time, although other derivatives did not significantly affect the sleeping time. The cataleptogenic effects of monofluoro- and 4-bromo-CBN were stronger than that of CBN. 4-Bromo-CBN exhibited a significant prolongation of seizure latency induced by pentylenetetrazol. These data suggest that halogenation of CBN modifies the pharmacological profile of the cannabinoid.

Animals↗

PubMed1998

Synthesis and pharmacological activities in mice of halogenated delta 9-tetrahydrocannabinol derivatives.

Seven halogenated derivatives of delta 9-tetrahydrocannabinol (delta 9-THC, 1) substituted on the aromatic ring at the 2 and/or 4 position, 2 (4)-fluoro- (2), 2,4-difluoro- (3), 2-chloro- (4), 2-bromo- (5), 2,4-dibromo- (6), 2-iodo- (7) and 2,4-diiodo-delta 9-THC (8) were synthesized and pharmacological effects such as catalepsy, anticonvulsant effects, hypothermia, pentobarbital-induced sleep prolongation and locomotor activity evaluated by intracerebroventricular (i.c.v., 25 micrograms/head) and intravenous (i.v., 5 or 10 mg/kg) injections in mice. The cataleptogenic effects of 2 and 5 were about three-quarters and two-thirds, respectively, compared to those of 1 (i.v.), though other derivatives were much less active (i.c.v. and i.v.). 2 (for clonic seizures) exhibited a significant prolongation of seizure latency induced by pentylenetetrazol (i.v.). Hypothermic effects of monohalogenated derivatives were comparable to 1 when administered by i.v. injection, whereas the effects of dihalogenated derivatives of 1 were attenuated. In contrast, 3 and 8 exhibited a significant hyperthermic effect in mice. In synergy with pentobarbital, 4 and 5 exhibited a significant prolongation of sleeping time by 1.6- and 1.8-fold, respectively, compared with control (32.4 +/- 2.5 min), although other derivatives did not affect significantly the sleeping time (i.c.v.). However, by i.v. injection, 2, 4, 5 and 7 significantly prolonged pentobarbital-induced sleeping time and reduced locomotor activity. The sleep prolonging effects of 2, 4 and 7 (10 mg/kg, i.v.) were as potent as that of 1 (5 mg/kg, i.v.). 5 and 7 were the most potent derivatives among the synthetic cannabinoids examined in the present study. These results indicate that halogenation of 1 leads to modification of the pharmacological profile of THC.

Animals↗

PubMed2005

Hemolytic potential of structurally related aniline halogenated hydroxylamines.

This study was undertaken to investigate the hemolytic potential of several structurally related aniline halogenated phenylhydroxylamines based on their decreasing electro negativity. The compounds compared are phenylhydroxylamine (PHA) and para-fluoro-, para-bromo-, and para-iodo-phenylhydroxylamines. Red blood cells of male Sprague-Dawley rats were labeled with radioactive chromium-51 and exposed to the test agent before being infused into the tail vein of isologous rats. The time course of blood radioactivity was monitored. The stability of some selected halogenated aniline analogs was also determined in blood. All four tested hydroxylamines produced dose-dependent reduction in the circulating labeled red blood cells indicating their destruction and loss. The most pronounced reduction was observed at doses from 175 to 250 microM. The dose of 100 microM appeared to be the threshold limit. The para-iodo-PHA was two times more toxic than para-fluoro-PHA in the destruction of red blood cells in rats.

Anemia, Hemolytic↗

PubMed1988

Effect of phenol and halogenated phenols on energy transfer reactions of rat liver mitochondria.

The in vitro effects of phenol and p-halogenated phenols on mitochondrial energy transfer reactions were examined using isolated rat liver mitochondria. The relationship between physiochemical properties of phenolic compounds and their effects on mitochondria were studied. Phenol and p-halogenated phenols induced the release of K+ ions from mitochondria, suggesting a change in permeability to K+ ions. A decrease in the respiratory control index, an increase in K+ release and stimulation of latent ATPase activity were observed with these compounds in the descending order of p-iodophenol, p-bromophenol, p-chlorophenol, p-fluorophenol and phenol. The concentrations of the phenolic compounds resulting in fifty percent inhibition of the respiratory control index and those resulting in fifty percent release of K+ ions significantly correlated with Hammett's substituent constant (sigma) and the hydrophobic binding constant (pi) of the compounds.

Adenosine Triphosphatases↗

PubMed2005

Co-amendment with halogenated compounds enhances anaerobic microbial dechlorination of 1,2,3,4-tetrachlorodibenzo-P-dioxin and 1,2,3,4-tetrachlorodibenzofuran in estuarine sediments.

Halogenated coamendments enhanced dechlorination of 31 microM of spiked 1,2,3,4-tetrachlorodibenzo-p-dioxin (TeCDD) and 49 microM of spiked 1,2,3,4-tetrachlorodibenzofuran (TeCDF) in sediments from San Diego Bay (CA, USA) and Tuckerton (NJ, USA). Dechlorination of 1,2,3,4-TeCDD occurred to a greater extent under methanogenic than under sulfate-reducing conditions. The most effective stimulation of 1,2,3,4-TeCDD dechlorination occurred with coamendment of 25 microM of 1,2,3,4-tetrachlorobenzene (TeCB), 2,3,4,5-tetrachloroanisole (TeCA), 2,3,4,5-tetrachlorophenol, or 2',3',4'-trichloroacetophenone plus 500 microM lactate and 500 microM propionate as electron donors. The 1,2,3,4-TeCDD dechlorination was evident after three months and sequentially produced mainly 1,2,4-trichlorodibenzo-p-dioxin, 1,3-dichlorodibenzo-p-dioxin, and 2-monochlorodibenzo-p-dioxin (MCDD). Monobromophenols (2-bromo-, 3-bromo-, and 4-bromophenol), monochlorophenols (2-chloro-, 3-chloro-, and 4-chlorophenol), 2,3,5,6-tetrachlorobenzoate, or electron donors alone stimulated less 1,2,3,4-TeCDD dechlorination, with activity apparent only after six months. The 1,2,3,4-TeCDD dechlorination produced 50 mol % 2-MCDD after six months in sediments from the more contaminated Graving Dock and Paleta Creek sites in San Diego Bay. The 1,2,3,4-TeCDD dechlorination by sediments from the less contaminated Shelter Island site in San Diego Bay and in pristine Tuckerton sediments did not produce 2-MCDD. Dechlorination of 1,2,3,4-TeCDF to tri- and dichlorinated daughter products was significantly enhanced by TeCB and TeCA. These results suggest that halogenated aromatic compounds with structural similarity to 1,2,3,4-TeCDD/F stimulate bacteria with the ability to dechlorinate chlorinated dibenzo-p-dioxin and furans.

Anaerobiosis↗

PubMed2002

Application of a pentafluorobenzyl bromide derivatization method in gas chromatography/mass spectrometry of trace levels of halogenated phenols in air, water and sediment samples.

An analytical method using pentafluorobenzyl bromide (PFBB) derivatization and gas chromatography/mass spectrometry (GC/MS) has been applied to identify and quantify chloro-, bromo- and dichlorophenols in air, water and sediment samples. Phenols in air sample were collected with a PS-2 Sep-PAK cartridge, and eluted with 2-propanol. For water and sediment samples, liquid-liquid extraction with dichloromethane was carried out, and the solvent was exchanged to 2-propanol. The phenols in the solution reacted with PFBB to form the corresponding pentafluorobenzyl esters. After extracting the derivatives into hexane, the determination was carried out by GC/MS with selected-ion monitoring. The detection limits of phenols in air, water and sediment were 0.0033 - 0.0073 microg/m3, 0.0066 - 0.0147 microg/L and 0.33 - 0.73 microg/kg, respectively. More than 90% recoveries of the halogenated phenols were obtained from real environmental samples spiked by the halogenated phenols. The three isomers of mono-chlorophenols were detected in sediment samples in the range of 5.2 - 9.2 microg/kg in wet weight basis.

Air↗

PubMedDate not supplied

The hepatic interaction of aliphatic alcohols with halogenated hydrocarbons.

As has been noted, advancement in understanding of chemical interactions requires an integrated approach. Given the large number of binary mixtures of aliphatic alcohols and halogenated hydrocarbons that can be formulated, and because limitations of time and resources make it impossible to test them all, careful thought should be given to selection of pairs for laboratory experimentation. For any given pair of chemicals, the type of interaction (addition, synergism, antagonism, potentiation) should be determined and described by appropriate experimental designs and statistical methodology. This has been done for various alcohol-halocarbon mixtures. Work to expand our understanding of the mechanism(s) underlying the interaction of aliphatic alcohols and halogenated hydrocarbons would be particularly useful, as an improved mechanistic understanding would improve our ability to extrapolate across dose levels (from high laboratory exposure concentrations to typical human environmental exposure concentrations) and across species (from laboratory animals to humans).

Alcohols↗

PubMed1982

Bioactivation of halogenated hydrocarbons.

Halogenated hydrocarbons are an economically and toxicologically important group of chemicals. These compounds may produce toxic effects after metabolism to stable, but toxic, products or to reactive, electrophilic intermediates. The biotransformation reaction may involve oxidative or reductive reactions or may proceed with no change in oxidation state. The bioactivation reactions are catalyzed most frequently by cytochrome P-450-dependent monooxygenases, but glutathione S-transferases may also catalyze bioactivation reactions. Detailed reaction mechanism studies are useful in understanding the biotransformation and bioactivation pathways of halogenated hydrocarbons.

Biotransformation↗

PubMed1990

Potential uses of combined halogen disinfectants in poultry processing.

Five organic N-halamine compounds (combined halogen disinfectants) were compared for their bactericidal activities against Salmonella typhimurium under controlled pH and temperature. All five compounds were effective as bactericides in demand-free buffers ranging from pH 5.0 to 9.0 and treatment temperatures from 4 to 48 C. The range of contact times necessary for a 99.9999% inactivation of viable cells was from .22 to 29 min, depending on the halogen concentration, temperature, and pH of the demand-free buffer. Two of the compounds (3-chloro-4,4-dimethyl-2-oxazolidinone and 1,3-dichloro-4,4,5,5-tetramethyl-2-imidazolidinone) were found to have considerable promise in high-temperature applications, and a third compound (1-bromo-3-chloro-4,4,5,5-tetramethyl-2-imidazolidinone) was more suitable for low-temperature treatments.

Animals↗

PubMed1990

Combined halogen disinfectants in poultry processing.

Three organic N-halamine compounds (combined halogen disinfectants) were compared with free chlorine (as calcium hypochlorite) as bactericides against Salmonella typhimurium and unidentified normal poultry bacterial flora under controlled conditions of pH, temperature, and halogen demand similar to those encountered in poultry processing. Two of the compounds (3-chloro-4,4-dimethyl-2-oxazolidinone and 1,3-dichloro-4,4,5,5-tetramethyl-2-imidazolidinone) at a concentration of 50 mg/L were found to cause a 99.9999% decline in viable organisms in less than 1 min at 48 C, whereas a third compound (1-bromo-3-chloro-4,4,5,5-tetramethyl-2-imidazolidinone) was found to be less suitable (5.6 min to 99.9999% decline under the same conditions).

Animals↗

PubMed2003

Degradation of halogenated aliphatic compounds utilizing sequential anaerobic/aerobic treatments.

The objective of this research was to determine if either methanogenic or sulfidogenic reductive dechlorination could survive an alternating anaerobic/aerobic sequence to biologically transform halogenated aliphatic hydrocarbons (HACs), specifically tetrachloroethylene (PCE), trichloroethylene (TCE), cis-1,2 dichloroethylene (cDCE), trans-1,2 dichloroethylene (tDCE), 1,1 dichloroethylene (1, 1DCE) and vinyl chloride (VC). This ability was considered to be a necessary prerequisite for complete anaerobic/aerobic mineralization of halogenated aliphatic hydrocarbons by a single microbial consortia. Chlorinated solvents, which are among the most common groundwater contaminants, have been partially dechlorinated using single-stage anaerobic environmental treatment strategies. Various types of bacteria typically reductively dechlorinate PCE and TCE to cDCE and VC in an anaerobic environment, including methanogens, sulfidogens, and homoacetogens. The problem lies in the fact that reductive dechlorination typically leads to an accumulation of daughter compounds (cDCE, VC) which are more toxic than their parent compounds (PCE, TCE). Furthermore, PCE and (to a lesser extent) TCE, are resistant to dechlorination in aerobic environments. In contrast, VC and cDCE are readily oxidized co-metabolically in an aerobic environment by methanotrophic bacteria, and others using oxygenases (e.g. toluene oxidizers). Results from this research showed that both methanogenic and sulfidogenic reductive dechlorination could resume after transient exposures to both oxygen and hydrogen peroxide (H2O2). In fact, for cycles as frequent as 10 days between aerobic treatment cycles, reductive dechlorination was observed to resume at rates at least as rapid as microcosms not exposed to aerobic treatments.

Bacteria, Aerobic↗

PubMed1992

A gas-chromatographic determination of the ppb levels of volatile halogenated hydrocarbons in water for injections.

Some volatile halogenated hydrocarbons have been found in commercial large volume parenterals (LVPs) prepared from untreated or treated (disinfected) water. To monitor the presence of volatile halogenated hydrocarbons in the source water and also in the water for injections, a low cost and sufficiently simple procedure has been developed, specifically for the following components: 1,1,1 trichloroethane, 1,1,2 trichloroethylene, 1,1,2,2 tetrachloroethylene, carbon tetrachloride, chloroform, dichlorobromomethane and dibromochloromethane. A Head-space technique coupled with ECD-gaschromatography was used. The procedure is thoroughly discussed in the article, including the results of a ring test for a preliminary validation of this method.

Chromatography, Gas↗

PubMedDate not supplied

[Presence of disinfection by-products (DBPs) and other halogenated compounds in drinking water samples collected in the areas of Modena and Parma].

The Authors report data about the presence of Disinfection By-Products (DBPs) and other halogenated compounds in drinking water samples collected in the areas of Modena and Parma (20 water supplies). Trihalomethanes, chlorite and chlorate (only in water samples treated with chlorine dioxide), and halogenated compounds were investigated. On the whole, trihalomethanes were evidenced in the 85% of the samples (n. 285) at low levels, while chlorite and chlorate were present in the 67% and 63% of the treated samples with chlorine dioxide (257 samples). Chlorite mean and median values were 225.70 microg/l and 136.75 microg/l respectively, ranging from 20 to 2000 microg/l. Chlorate concentrations were lower than chlorite: the mean value was 102.93 mg/l, while median level was 50 microg/l (range: 20-1500 microg/l). The high concentrations of chlorite and the wide range of values within each municipality plant in Modena and Parma suggest to investigate further in order to evaluate the human exposure in drinking water thoroughly.

Chlorine Compounds↗