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At least 109 records · Page 6Linked to original sources
PubMed2003

Phytotoxicity of 2,4,6-trinitrotoluene (TNT) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) in spiked artificial and natural forest soils.

Toxicity of 2,4,6-trinitrotoluene (TNT) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) using two terrestrial plant species, lettuce (Lactuca sativa) and barley (Hordeum vugare), was assessed in artificial soil (silica) and forest soil. Lettuce emergence was significantly decreased after 5 days of exposure to TNT nominal spiked concentrations >/= 1,040 mg/kg dry soil in silica. Barley emergence was significantly reduced after 14 days of exposure at initial (t = 0) TNT concentrations >/= 55.9 +/- 4.5 mg/kg dry soil in silica and at >/= 291.9 +/- 42.8 mg/kg dry forest soil. Biomasses of shoot and roots of barley seeds were significantly reduced after 14 days of exposure at TNT initial exposure concentrations >/= 55.9 +/- 4.5 (LOEC) mg/kg dry soil in silica. Results were similar with the forest soil (LOEC = 91.4 +/- 7.9 mg TNT/kg dry soil) using the root growth parameter, but the shoot biomass was reduced only at concentrations >/= 291.9 +/- 42.8 mg TNT/kg dry soil. Plants were not affected by an HMX exposure up to 3,320 +/- 1,019 mg/kg dry soil using silica or 1,866 +/- 438 mg/kg dry soil using a forest soil. During the 14-day experiments, TNT was partially transformed in the spiked soil samples, as indicated by the presence of its amino metabolites (2-ADNT and 4-ADNT). Higher quantities of metabolites were detected in forest soils having higher initial TNT concentrations (</= 1,849.4 +/- 228.2 mg/kg) compared to silica (</= 239.3 +/- 88.0 mg TNT/kg). After 14 days, TNT concentrations in spiked silica and forest soil were reduced up to 80.5% at 55.9 +/- 4.5 mg/kg initial concentration and 94.4% at 91.4 +/- 7.9 mg/kg initial concentration, respectively. Data indicate that TNT is the probable phytotoxicant because it decreased plant emergence and growth in the presence and absence of the ADNT metabolites.

Azocines↗
PubMed2006

Biodegradation of the cyclic nitramine explosives RDX, HMX, and CL-20.

Cyclic nitramine explosives are synthesized globally mainly as military munitions, and their use has resulted in environmental contamination. Several biodegradation pathways have been proposed, and these are based mainly on end-product characterization because many of the metabolic intermediates are hypothetical and unstable in water. Biodegradation mechanisms for cyclic nitramines include (a) formation of a nitramine free radical and loss of nitro functional groups, (b) reduction of nitro functional groups, (c) direct enzymatic cleavage, (d) alpha-hydroxylation, or (e) hydride ion transfer. Pathway intermediates spontaneously decompose in water producing nitrite, nitrous oxide, formaldehyde, or formic acid as common end-products. In vitro enzyme and functional gene expression studies have implicated a limited number of enzymes/genes involved in cyclic nitramine catabolism. Advances in molecular biology methods such as high-throughput DNA sequencing, microarray analysis, and nucleic acid sample preparation are providing access to biochemical and genetic information on cultivable and uncultivable microorganisms. This information can provide the knowledge base for rational engineering of bioremediation strategies, biosensor development, environmental monitoring, and green biosynthesis of explosives. This paper reviews recent developments on the biodegradation of cyclic nitramines and the potential of genomics to identify novel functional genes of explosive metabolism.

Amines↗
PubMed2000

Microbial degradation of explosives: biotransformation versus mineralization.

The nitroaromatic explosive 2,4,6-trinitrotoluene (TNT) is a reactive molecule that biotransforms readily under both aerobic and anaerobic conditions to give aminodinitrotoluenes. The resulting amines biotransform to give several other products, including azo, azoxy, acetyl and phenolic derivatives, leaving the aromatic ring intact. Although some Meisenheimer complexes, initiated by hydride ion attack on the ring, can be formed during TNT biodegradation, little or no mineralization is encountered during bacterial treatment. Also, although the ligninolytic physiological phase and manganese peroxidase system of fungi can cause some TNT mineralization in liquid cultures, little to no mineralization is observed in soil. Therefore, despite more than two decades of intensive research to biodegrade TNT, no biomineralization-based technologies have been successful to date. The non-aromatic cyclic nitramine explosives hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) lack the electronic stability enjoyed by TNT or its transformed products. Predictably, a successful enzymatic change on one of the N-NO2 or C-H bonds of the cyclic nitramine would lead to a ring cleavage because the inner C-N bonds in RDX become very weak (<2 kcal/mol). Recently this hypothesis was tested and proved feasible, when RDX produced high amounts of carbon dioxide and nitrous oxide following its treatment with either municipal anaerobic sludge or the fungus Phanaerocheate chrysosporium. Research aimed at the discovery of new microorganisms and enzymes capable of mineralizing energetic chemicals and/or enhancing irreversible binding (immobilization) of their products to soil is presently receiving considerable attention from the scientific community.

Aerobiosis↗
PubMed1998

Metabolism of explosive compounds by sulfate-reducing bacteria.

The metabolism of various explosive compounds-1,3,5-trinitrobenzene (TNB), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX)-by a sulfate-reducing bacterial consortium, Desulfovibrio spp., was studied. The results indicated that the Desulfovibrio spp. used all of the explosive compounds studied as their sole source of nitrogen for growth. The concentrations of TNB, RDX, and HMX in the culture media dropped to below the detection limit (<0.5 ppm) within 18 days of incubation. We also observed the production of ammonia from the nitro groups of the explosive compounds in the culture media. This ammonia served as a nitrogen source for the bacterial growth, and the concentration of ammonia later dropped to <0.5 mg/L. The sulfate-reducing bacteria may be useful in the anaerobic treatment of explosives-contaminated soil.

Ammonia↗
PubMed2001

[The Ca(2+) sensitizers CGP 48506 and EMD 57033, but not the Na(+) channel modulator BDF 9148, prolong relaxation in isolated cardiomyocytes of the guinea pig].

The sodium channel modulator DPI 201-106 has been described to posses Ca(2+)-sensitizing properties. Therefore, the present study investigated the inotropic effect of the Na(+)-channel modulator BDF 9148 (1 microM), a congener of DPI 201-106, in comparison with the Ca(2+)-sensitizers CGP 48506 (1-50 mumol/l) and EMD 57033 (1-30 mumol/l) in electrically driven left ventricular cardiomyocytes isolated from guinea pigs. The changes of the contraction amplitude in comparison to the basal cell shortening (cell shortening in micron and %) were continuously recorded with a one-dimensional high speed camera. BDF 9148, CGP 48506, and EMD 57033 exerted a significant increase in the contraction amplitude (p < 0.05 vs. control). The maximal positive inotropic effects of CGP 48506 (50 mumol/l) and EMD 57033 (30 mumol/l) were +249 +/- 30% and +226 +/- 28%, respectively. The corresponding value for BDF 9148 (1 mumol/l) was +176 +/- 16%. However, only the Ca(2+)-sensitizers CGP 48506 and EMD 57033, but not BDF 9148, prolonged the contractile twitch. Especially in patients with an already enhanced intracellular myocardial Ca(2+)-concentration, Ca(2+)-sensitizers, which impair relaxation, may be disadvantageous for therapeutical use despite their positive inotropic effect.

Animals↗
PubMed2002

Effects of the Ca2+ sensitizers EMD 57033 and CGP 48506 on myocardial contractility and Ca2+ transients in human ventricular and atrial myocardium.

Ca2+ sensitizers like EMD 57033 (EMD) and CGP 48506 (CGP) may be advantageous for the treatment of human heart failure, as they increase force of contraction without increasing the intracellular Ca2+ transients or energy consumption. However, whether or not Ca2+ sensitizers differ in their mode of action in human myocardium is not fully understood. The present study investigates the influence of EMD and CGP on force of contraction (FOC) and the intracellular Ca2+ transient (fura-2 ratio method) in left ventricular papillary muscle strips from left ventricular failing human myocardium (DCM, n = 28) as well as in right atrial trabeculae (RA, n = 21) obtained from patients undergoing cardiac bypass surgery. In isolated trabeculae of DCM, FOC was more efficacious and potently increased after application of EMD (EC50 EMD: 4.7 +/- 1.0 mumol/l, max. PIE EMD: + 12.0 +/- 2.0 mN/mm2) than CGP (EC50: 16.9 +/- 7.6 mumol/l, max. PIE: +6.4 +/- 2.8 mN/mm2). Similar results were obtained in RA. Application of carbachol (100 mumol/l) had no effect on the positive inotropic effect of EMD or CGP. Both Ca2+ sensitizers significantly increased time to half peak relaxation as well as diastolic tension in DCM. EMD (10 mumol/l) and CGP (30 mumol/l) did not affect the Ca2+ transients in RA. The Ca2+ sensitizers EMD and CGP increase cAMP and Ca2+ independently from the force of contraction in the human myocardium. However, their therapeutic use in human heart failure may be limited as they impair relaxation.

Azocines↗
PubMed2005

Biodegradation of cyclic nitramines by tropical marine sediment bacteria.

Undersea deposition of unexploded ordnance (UXO) constitutes a potential source of contamination of marine environments by hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX). The goal of the present study was to determine microbial degradation of RDX and HMX in a tropical marine sediment sampled from a coastal UXO field in the region of Oahu Island in Hawaii. Sediment mixed cultures growing in marine broth 2216 (21 degrees C) anaerobically mineralized 69% or 57% (CO2, 25 days) of the total carbon of [UL-14 C]-RDX (100 microM) or [UL-14 C]-HMX (10 microM), respectively. As detected by PCR-DGGE, members of gamma-proteobacteria (Halomonas), sulfate-reducing delta-proteobacteria (Desulfovibrio), firmicutes (Clostridium), and fusobacterium appeared to be dominant in RDX-enrichment and/or HMX-enrichment cultures. Among 22 sediment bacterial isolates screened for RDX and HMX biodegradation activity under anaerobic conditions, 5 were positive for RDX and identified as Halomonas (HAW-OC4), Marinobacter (HAW-OC1), Pseudoalteromonas (HAW-OC2 and OC5) and Bacillus (HAW-OC6) by their 16S rRNA genes. Sediment bacteria degraded RDX to N2O and HCHO via the intermediary formation of hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) and methylenedinitramine. The present findings demonstrate that cyclic nitramine contaminants are likely to be degraded upon release from UXO into tropical marine sediment.

Azocines↗
PubMed1999

The effect of cotinine on nicotine- and cocaine-induced dopamine release in the nucleus accumbens.

Cotinine is the major metabolite of nicotine. Nicotine is rapidly metabolized and has a short half-life, but cotinine is metabolized and eliminated at a much lower rate. Because of the resulting increase with time in the cotinine to nicotine ratio in the body, including in the brain, it is of interest to examine the effect of cotinine on nicotine-induced changes. In studies on conscious, freely-moving rats, intravenous administration of either nicotine or cocaine induced the release of dopamine in the nucleus accumbens, as assayed by microdialysis. Prior intravenous administration of a high dose of cotinine (500 microg/kg) inhibited this nicotine- or cocaine-induced dopamine release. The action of cotinine does not seem to occur through its effect on the metabolism of nicotine or on its binding at the receptor site, because cotinine, unlike nicotine, does not affect the binding of the nicotinic ligand cytisine. The findings suggest that cotinine affects a putative component of the reward mechanism, and as such could have therapeutic value.

Alkaloids↗
PubMed2004

Ablation of primary afferent terminals reduces nicotinic receptor expression and the nociceptive responses to nicotinic agonists in the spinal cord.

A variety of studies indicate that spinal nicotinic acetylcholine receptors modulate the behavioral and autonomic responses elicited by afferent stimuli. To examine the location of and role played by particular subtypes of nicotinic receptors in mediating cardiovascular and nociceptive responses, we treated neonatal and adult rats with capsaicin to destroy C-fibers in primary afferent terminals. Reduction of C-fiber terminals was ascertained by the loss of isolectin B4, CGRP and vanilloid receptors as monitored by immunofluorescence. Receptor autoradiography shows a reduction in number of epibatidine binding sites following capsaicin treatment. The reduction is particularly marked in the dorsal horn and primarily affects the class of high affinity epibatidine binding sites thought to modulate nociceptive responses. Accompanying the loss of terminals and nicotinic binding sites were significant reductions in the expression of alpha 3, alpha 4, alpha 5, beta 2 and beta 4 nicotinic receptor subunits in the superficial layers of the spinal cord as determined by antibody staining and confocal microscopy. The loss of nicotinic receptors that follows capsaicin treatment results in attenuation of the nociceptive responses to both spinal cytisine and epibatidine. Capsaicin treatment also diminishes the capacity of cytisine to desensitize nicotinic receptors mediating nociception, but it shows little effect on intrathecal nicotinic agonist elicited pressor and heart rate responses. Hence, our data suggest that alpha 3, alpha 4, alpha 5, beta 2 and beta 4 subunits of nicotinic receptors are localized in the spinal cord on primary afferent terminals that mediate nociceptive input. A variety of convergent data based on functional studies and subunit expression suggest that alpha 3 and alpha 4, in combination with beta 2 and alpha 5 subunits, form the majority of functional nicotinic receptors on C-fiber primary afferent terminals. Conversely, spinal nicotinic receptors not located on C-fibers play a primary role in the spinal pathways evoking spinally coordinated autonomic cardiovascular responses.

Alkaloids↗
PubMed1990

Molecular pharmacological aspects of antiarrhythmic activity. I. Class I and class III compounds and lipid peroxidation.

The effect of nineteen antiarrhythmic agents on nonenzymatic lipid peroxidation, using rat hepatic microsomes, was studied. Lipid peroxidation was induced by Fe2(+)-ascorbic acid and assayed spectrophotometrically by measuring the 2-thiobarbituric acid reactive material. The compounds tested have various structural characteristics and represent class I and III of antiarrhythmics as classified by Vaughan Williams. The RM values, derived from reversed-phase thin-layer chromatography, were determined, and sigma f values calculated in order to correlate lipophilicity and antioxidant activity. The antiarrhythmics studied inhibited lipid peroxidation to various degrees. No apparent structural factor could definitely be attributed to this effect and antioxidants are found among both class I and class III compounds. There is a trend toward a parabolic relationship between antioxidant potency and lipophilicity. Three of the tested antiarrhythmics, namely the lipophilic amiodarone, aprindine and asocainol, were very potent antioxidants, and a further investigation of concentration and time dependency of lipid peroxidation was performed. It is suggested that, at least for some antiarrhythmic drugs, antioxidant activity may be part of their mode of action, and that it may form an additional beneficial feature for the treatment of cardiac failure.

Amiodarone↗
PubMed1994

Interaction of p-aminophenyldichloroarsine, an arsenical with specificity for vicinal cysteines, with [3H]cytisine binding sites in rat brain membranes.

The arsenical compound p-aminophenyldichloroarsine (APA) is selective for spatially close thiols with which it forms a stable complex. The alpha subunits of nicotinic acetylcholine receptors are defined by the presence of a pair of adjacent cysteines close to the agonist binding site. Here the interaction of APA with [3H]cytisine binding sites, which correspond to the major subtype of nicotinic receptors in rat brain has been examined. Incubation of brain membranes with 10 microM APA abolished [3H]cytisine binding. The action of APA was dependent on prior reduction of sulphydryls with dithiothreitol. APA effects could not be reversed by oxidizing agents but could be reversed by the antiarsenical reagent 2,3-dimercapto-1-propane sulphonic acid. Under the conditions used, the concentration of APA producing a half-maximal decrease in binding was 130 nM. The loss of [3H]cytisine binding was due to a decrease in the number of binding sites (Bmax) with no effect on affinity for the radioligand (Kd). Nicotinic ligands failed to protect against the reduction and arsenylation of neuronal receptor sites. These observations are consistent with the potent interaction of APA with this neuronal nicotinic receptor.

Alkaloids↗
PubMed1995

Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia.

This study tests the hypothesis that nicotinic cholinergic receptors, including those sensitive to the antagonist alpha-bungarotoxin, are decreased in the hippocampus of schizophrenics. The hypothesis is derived from the finding that alpha-bungarotoxin causes a defect in the inhibitory gating of auditory-evoked potentials in laboratory animals that resembles a defect in auditory sensory gating observed in schizophrenics. Nicotine transiently normalizes this psychophysiological deficit in schizophrenic patients. Postmortem brain tissue was obtained from eight schizophrenic and eight age-matched nonschizophrenic subjects. Sections of the hippocampus were labeled with [125I alpha-bungarotoxin and imagined by autoradiography. Binding of the nicotinic agonist [3H]-cytisine was determined in tissue homogenates. alpha-Bungarotoxin labeled a population of putative interneurons in the hippocampus, primarily in the dentate gyrus and the CA3 region of Ammon's horn. This labeling was significantly decreased in the tissue from the schizophrenic patients, with seven or eight patients below the range of the nonschizophrenic subjects. There was also a significant decrease in the binding of cytisine. The results were not related to generalized hippocampal cell loss, drug exposure at time of death, or smoking history. This initial study suggests that schizophrenic patients have fewer nicotinic receptors in the hippocampus, a condition which may lead to failure of cholinergic activation of inhibitory interneurons, manifest clinically as decreased gating of response to sensory stimulation.

Adult↗
PubMed1988

[3H](-)nicotine binding sites in fetal human brain.

The development of putative nicotinic binding sites in brains from human fetuses of 12-19 weeks gestation was studied. The binding of [3H](-)nicotine to fetal human brain membranes, using a rapid filtration method, was saturable and stereospecific. Scatchard analysis revealed a single class of high affinity sites with a Kd of 1.5 +/- 0.5 nM and a Bmax of 4.5 +/- 1.9 fmol/mg protein (n = 11). [3H](-)nicotine binding increased between the ages of 12 and 19 weeks in human fetal brain (r = 0.63, n = 20, P less than 0.01). In competition studies nicotinic agonists were the most effective in inhibiting [3H](-)nicotine binding whereas antagonists were relatively ineffective. Ki values for displacing ligands in the presence of [3H](-)nicotine were: cytisine, 1.6 nM; (-)nicotine, 16 nM; (+) nicotine, 510 nM; dihydro-beta-erythroidine, 1.9 microM; dimethyl-4-phenylpiperazinium, 6.5 microM; choline chloride, 25 microM. Atropine and alpha-bungarotoxin failed to inhibit binding up to 50 microM. Comparison of dissected brain regions revealed regional variations in the density of nicotinic binding sites: specific binding of [3H](-)nicotine was greatest in the nucleus basalis of Meynert, globus pallidus, caudate-putamen and thalamus, and lowest in the medulla. These results are interpreted in relation to the development of functional cholinergic transmission in human fetal brain, and the potential vulnerability of this system to maternal tobacco usage.

Alkaloids↗
PubMed1993

Characterization of [3H]cytisine binding to human brain membrane preparations.

The binding characteristics of [3H]cytisine, a putative CNS nicotinic receptor ligand, were examined in 4 regions of the human brain. [3H]Cytisine was found to bind non-cooperatively with high affinity to a single site in tissue homogenates and to exhibit low non-specific association. The binding characteristics of this ligand were evaluated in thalamus at 4 degrees C and 24 degrees C. The association constants were found to be 0.234 and 0.308 min-1 nM-1, while the dissociation constants were 0.007 and 0.098 min-1, respectively. Saturation analysis of thalamus revealed the equilibrium Kd to be 147 pM (4 degrees C) and 245 pM (24 degrees C), values in good agreement with those determined kinetically. The Hill coefficient varied slightly between brain regions; however, the mean values in all regions examined were close to 1.0 at 0.95 +/- 0.03 (4 degrees C) and 0.91 +/- 0.04 (24 degrees C). [3H]Cytisine binding could be displaced using both nicotinic agonists and antagonists. Cytisine was the most potent displacer of [3H]cytisine binding with an Ki of 250 pM. Nicotine and acetylcholine were also potent displacers with Ki values of 1.8 and 8.1 nM, respectively. The nicotinic antagonists alpha-bungarotoxin and mecamylamine were ineffective competitors for the [3H]cytisine binding site while dihydro-beta-erythroidine had an Ki value of 109 nM. Thalamus showed the highest density of cytisine binding sites of all the regions examined (48 fmol/mg protein) while the hippocampus, cingulate gyrus and the cortex showed Bmax values of 18.9, 19.3 and 8.8 fmol/mg protein, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Cytisine-induced behavioral activation: delineation of neuroanatomical locus of action.

Systemic injections of nicotine increase locomotor activity. The present study was designed to determine whether there is a circumscribed region in the ventral tegmentum that mediates the locomotor-activating effects of nicotine. The mapping technique was used to delineate this region: bilateral injections of cytisine (1 nmol/0.5 microliters per side) were made into sites in and around the ventral tegmentum and the amount of locomotion associated with each site was quantified. The distribution of injection sites spanned between 0.8 and 4.6 mm posterior to bregma. The amount of locomotion varied with relation to the area into which cytisine was injected and a region was identified within which injections of cytisine preferentially increased locomotion. This region appears to have reasonably well-defined anterior and posterior boundaries. Since a portion of the delineated area overlaps the dopamine-containing cell-body region, the possibility remains that the activation of the mesolimbic dopamine system may contribute to the behavioral activation associated with ventral tegmental injections of cytisine. This same system may contribute to the locomotor-activating effects associated with systemic injections of nicotine.

Alkaloids↗
PubMed1994

Clozapine attenuates the discriminative stimulus properties of (-)-nicotine.

Rats were trained to discriminate 1.9 mumol/kg (-)-nicotine (0.3 mg/kg) from saline in a standard two-bar operant conditioning paradigm with food reinforcement. The effect of neuronal nicotinic acetylcholine receptor (nAChR) agonists and antagonists were verified, and the participation of dopaminergic receptors subtypes in the expression of the (-)-nicotine cue was investigated with cis-flupentixol (D1-D2 antagonist), haloperidol (D2 antagonist) and clozapine (D4 antagonist). The stereoselectivity of the behavioral response was indicated by the 10-fold less sensitivity to (+)-nicotine in (-)-nicotine-trained rats. (+/-)-Anabasine and (-)-cytisine exhibited partial agonist profiles at the 1.9 mumol/kg dose while (-)-lobeline was devoid of any effect in doses up to 19 mumol/kg. (-)-Lobeline did not show antagonist properties in this paradigm. The nicotinic channel blockers mecamylamine, chlorisondamine and hexamethonium were inactive on their own but mecamylamine and chlorisondamine were able to block the effect of (-)-nicotine. Clozapine attenuated the (-)-nicotine cue while cis-flupentixol and haloperidol were ineffective. Similar doses of cis-flupentixol significantly blocked the locomotor stimulant effect of (-)-nicotine in rats indicating that blockade of dopaminergic receptors was achieved at the doses used in the drug discrimination studies. These data suggest that the discriminative stimulus properties of (-)-nicotine are mediated through neuronal nAChRs and involves the activation of dopaminergic receptors of the D4 subtype.

Alkaloids↗