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PubMed1998

Halogenated aromatic hydrocarbons suppress CA1 field excitatory postsynaptic potentials in rat hippocampal slices.

Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated biphenyls (PCBs) and dibenzo-p-dioxins (PCDDs), alter cognitive function and learning. The cellular basis of HAH-induced alteration of brain function is not well-understood. The hippocampus is a likely site of toxic action because of its well-known roles in learning and memory, as well as its propensity to accumulate environmental neurotoxicants. A hippocampal function that can be measured readily is evoked excitatory postsynaptic potentials (EPSPs), which are an index of excitatory synaptic function. In this study, effects of HAHs on EPSPs were characterized in hippocampal slices from adolescent to adult male Sprague-Dawley rats. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4-TCDD were used because these HAHs are prototypical potent and weak aryl hydrocarbon (Ah) receptor agonists, respectively. 2,2',5,5'-Tetrachlorobiphenyl (TCB) was used as a prototypical ortho-substituted PCB, which acts through Ah receptor-independent pathways. For each hippocampal slice, peak amplitudes of EPSPs during a 15-min recording period (1 recording/min) were averaged and used as baseline (100%). Subsequent EPSPs were expressed as percentage of baseline. TCDD and 1,2,3,4-TCDD did not alter EPSPs in slices from the middle third of the hippocampus. However, in ventral slices, TCDD significantly decreased EPSPs, whereas 1,2,3,4-TCDD was inactive. TCB decreased EPSPs in both middle and ventral slices at half-maximal stimulation. An unexpected reversal of inhibition was observed within 30 min of continuous application of TCDD or TCB. In ventral slices, L-type calcium channel blocker nifedipine blocked inhibition of EPSPs induced by TCDD but not EPSPs inhibited by TCB. These results suggest that, while TCB-induced inhibition of EPSPs occurs through an unknown mechanism, TCDD-induced inhibition of EPSPs was mediated by L-type calcium channel activity in a congener-specific manner.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Probing sister chromatid exchange formation with halogenated pyrimidines.

This communication describes the use of 6 different halogenated pyrimidine analogues, bromodeoxyuridine (BrdUrd), chlorodeoxyuridine (CldUrd), iododeoxyuridine (IdUrd), bromodeoxycytidine (BrdCyd), chlorodeoxycytidine (CldCyd), and iododeoxycytidine (IdCyd), to achieve sister chromatid differentiation (SCD) and evaluate sister chromatid exchange (SCE) formation in mitogen-stimulated human lymphocytes. Also included are a description of an in vivo experiment with BrdUrd, CldUrd, and IdUrd; a discussion of pyrimidine metabolism effects on SCEs; and the presentation of an update on the "conformation hypothesis" for SCE formation. This hypothesis revision includes a model that centers on the idea that the sum of the conformational alterations of the DNA polymerase-DNA template complex at replication is the controlling factor in SCE formation.

Animals↗
PubMed1987

Lack of cross-resistance between cytosine arabinoside and a new halogenated nucleoside analogue, 2-bromo-2'-deoxyadenosine in human acute myeloid leukaemia cells.

2-Bromo-2'-deoxyadenosine (BdA) is one of a group of recently synthesised halogenated deoxyadenosine analogues that are relatively resistant to inactivation by adenosine deaminase (ADA). Its activity has been studied in human acute myeloid leukemia (AML) in vitro. In these studies BdA behaved as a cycle-active, phase-active agent that blocked cells at the G1-S transition. It did not exhibit significant cross-resistance with cytosine arabinoside (Ara-C) in either clinical AML samples (from patients who exhibited Ara-C resistance in vivo) or in HL60 in which Ara-C resistance had been induced in vitro. Deoxycytidine kinase levels were not reduced in resistant lines. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase (ADA) inhibitor, with BdA produced a simple additive response without the dramatic synergism reported when it is used with deoxyadenosine. This is consistent with the idea that BdA is a poor substrate for ADA. This group of compounds warrants further investigation to determine their suitability for clinical use, especially in situations where Ara-C resistance is likely to be a problem.

Cell Line↗
PubMed1982

6-125I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) as a potential radio-halogenated anti-cancer agent: in vitro investigations and possible clinical implications.

6-125-I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) (6-125I-iodo-MNDP) has been synthesised and studied as the prototype of a class of potential radio-halogenated anti-cancer agents. The incorporated 125I provides Auger electron radiations which behave like high LET radiations in the treatment of tumours, though the accompanying X- and gamma-radiations make an undesirable contribution to the total body dose. The in vitro experiments reported show that 6-125I-iodo-MNDP is selectively concentrated in the cells of some human malignant tumours by factor of about 15 to 20 or more in relation to the cells of normal origin studied. On the basis of dosimetric considerations and comparison with clinical treatment with tritiated methylnaphthoquinol diphosphate, practical dosage of 6-125I-iodo-MNDP is suggested and clinical indications and safety of use are discussed. The types of tumour of particular interest are inoperable cases of carcinoma of the colon, carcinoma of the pancreas, malignant melanoma and osteosarcoma. Further investigations are in progress.

Animals↗
PubMed1984

Comparative metabolism and carcinogenicity of ring-halogenated 3,3-dimethyl-1-phenyltriazenes.

The objective of this study was to compare urinary metabolism of parent 3,3-dimethyl-1-phenyltriazene with that of its ring-substituted 1-(4-chlorophenyl)-3,3-dimethyltriazene and 1-(2,4,6-trichlorophenyl)-3,3-dimethyltriazene congeners, in an attempt to evaluate the molecular requirements for systemic carcinogenic activity. Complementary carcinogenicity assays were conducted at low equimolar dose levels using both 4- und 2,4,6-chlorinated and brominated analogues. Ring halogenation was found to prolong metabolic detoxification and to reduce carcinogenic activity.

Animals↗
PubMed1983

Induction of diphtheria toxin-resistant mutants in human cells by halogenated compounds.

The mutagenic power of 1,2-dichloroethane, 1,2-dibromoethane, 1,2-diiodoethane was tested in the human cell line, EUE. In our mutagenic system, based on selection against diphtheria toxin, the halogenated compounds, 1,2-dichloroethane and 1,2-dibromoethane revealed a strong mutagenic effect, whereas 1,2-diiodoethane was not mutagenic at a concentration allowing survival of 41%.

Cell Line↗
PubMed1994

Antitumor activity of halogen analogs of phosphoramide, isophosphoramide, and triphosphoramide mustards, the cytotoxic metabolites of cyclophosphamide, ifosfamide, and trofosfamide.

A series of halogen analogs of phosphoramide mustard, isophosphoramide mustard, and triphosphoramide mustard, the cytotoxic metabolites of the antitumor drugs cyclophosphamide, ifosfamide, and trofosfamide, respectively, was evaluated in vitro against human tumor cell lines and in vivo against experimental tumors to investigate the effect of replacement of chlorine with bromine or fluorine on the antitumor activity of the parent phosphoramide mustards. In the experimental tumors L1210 leukemia, B16 melanoma, mammary adenocarcinoma 16/C, and ovarian sarcoma M5076, the antitumor activity of the analogs was observed to be generally comparable with that of the parent mustards when chlorine was replaced by bromine but uniformly lower when chlorine was replaced by fluorine. Furthermore, the monobromo analog of isophosphoramide mustard displayed equal or somewhat greater activity in comparison with cyclophosphamide when evaluated against subcutaneously implanted L1210 leukemia with intraperitoneal drug treatment and against mammary adenocarcinoma 16/C.

Animals↗
PubMed1989

Highly conformationally constrained halogenated 6-spiroepoxypenicillins as probes for the bioactive side-chain conformation of benzylpenicillin.

The halogenated 6-spiroepoxypenicillins are a series of novel semisynthetic beta-lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3R-compounds possess notable Gram-positive antibacterial activity and potent beta-lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retain beta-lactamase inhibitory activity. Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3R-, and 3S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3R- and the 3S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains of both the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, 'bioactive' conformer for the classical beta-lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S2-subsite, specific for the side-chain aromatic moiety, and the 3 alpha-carboxylate functionality is presented.

Epoxy Compounds↗
PubMed1994

Inhibition of penicillin biosynthetic enzymes by halogen derivatives of phenylacetic acid.

The effect of phenylacetic acid (PAA) and several analogs on the activity of isopenicillin N synthase (IPNS) and acyl-CoA: 6-APA acyltransferase (AT) from Penicillium chrysogenum Wis 54-1255 has been tested. Whereas the substitution on the ring of a hydrogen atom by hydroxy-, methyl- or methoxy- groups did not cause any effect, the presence of halogens (Cl or Br) at positions 3 and/or 4 of PAA strongly inhibited these two enzymes. The replacement of hydrogen atoms by fluorine in certain positions also caused inhibition, but to a lesser extent.

Acyltransferases↗
PubMed1992

Neoplastic expression in murine cells induced by halogenated hydrocarbons.

The neoplastic expression in mouse embryo fibroblasts exposed to 1,2-dibromoethane and its chloroanalogue, 1,2-dichloroethane in vitro, was examined. Both substances are widely used as fumigants for carpet and upholstery, as gasoline additives, and as organic solvents. Both are known to be highly toxic, mutagenic, and carcinogenic agents. C3H10T1/2 cells treated with these haloalkanes exhibited altered morphology and were selected further by cloning in soft agar. Soft agar clones were found to induce a 100% multitumor occurrence in the nude mouse model. These results suggest that this pair of mutagens have altered the normal phenotype of mouse embryo cells, and these cells have become neoplastic. These neoplastic cell lines will be useful as an in vitro model to study the role of genetic changes in the transformation processes induced by halogenated hydrocarbons.

Animals↗
PubMed2006

Bioaccumulation of naturally occurring mixed halogenated dimethylbipyrroles in whale and dolphin products on the Japanese market.

Mixed halogenated dimethyl bipyrroles (HDBPs), which are thought to be produced naturally, were quantified in whale and dolphin products marketed for human consumption in Japan. The major component of HDBPs was 3,3',4,4'-tetrabromo-5,5'-dichloro-1,1'-dimethyl -2,2'-bipyrrole (Br(4)Cl(2)-DBP), accounting for 85% of the total of five HDBPs detected, followed by Br(3)Cl(2)-DBP. Mean concentrations of HDBPs ranged from 0.27 microg/g lipid (n = 31) in minke whale (Balaenoptera acutorostrata) from the northwest Pacific Ocean to 11.8 microg/g lipid (n = 33) in bottlenose dolphin (Tursiops trucatus) from the southwest Japanese coastal water. At higher levels, HDBPs made up 37% of the total organohalogen body burden in Dall's porpoise (Phocoenoides dalli), whereas the contribution was less than 8.9% in minke whales. In two data subsets from Baird's beaked whale (Berardius bairdii), the products from the Pacific Ocean contained significantly higher concentrations of HDBPs than those from the Sea of Japan. Furthermore, the geographical distribution of HDBPs did not resemble those of ubiquitous anthropogenic organochlorines, such as polychlorinated biphenyl (PCBs). Higher concentration ratios of SigmaHDBP/SigmaPCB and different patterns of HDBP congeners were observed in whale products from the Asia-Pacific as compared to non-Pacific Ocean mammals reported previously. These results support the hypothesis that HDBPs and anthropogenic organochlorines have different sources and that the consumption of HDBPs by Japanese individuals could be an exposure/health risk.

Animals↗
PubMed2002

Identification of hydroxylated PCB metabolites and other phenolic halogenated pollutants in human blood plasma.

A growing number of studies have reported phenolic halogenated compounds (PHCs) that are retained in the blood of humans and wildlife. These PHCs may be industrial chemicals; metabolites thereof, as in the case with polychlorobiphenylols (OH-PCBs); or of natural origin. The present study was aimed to identify hitherto unknown PHCs in human plasma with chemical structures that are consistent to PHCs known to possess endocrine-disrupting activity. For this purpose, samples of blood plasma from 10 randomly selected male blood donors from Sweden were pooled and analyzed by GC/ECD and GC/MS. Brominated, bromochlorinated, and chlorinated methyl derivatives of phenols and OH-PCBs were synthesized to be used as authentic reference standards. More than 100 PHCs were indicated in the plasma, and among those a total of 9 monocyclic brominated or chlorinated phenol-, guaiacol-, and/or catechol-type compounds were identified as their methylated derivatives. The two major compounds were 2,4,6-tribromophenol and pentachlorophenol. Thirty-eight OH-PCB congeners were structurally identified on two GC columns of different polarity. The origin of the OH-PCB metabolites in the context of their parent PCB congeners are suggested. Other PHCs identified in the male plasma were Triclosan (5-chloro-2-[2,4-dichlorophenoxy] phenol), a common bactericide; 4-hydroxy-heptachlorostyrene, a metabolite of octachlorostyrene; and 3,5-dibromo-2-(2,4-dibromophenoxy)phenol, a natural compound and a potential metabolite of polybrominated diphenyl ethers.

Adult↗
PubMed1997

Sensitivity of common tern (Sterna hirundo) embryo HepatocyteCultures to CYP1A induction and porphyrin accumulation by halogenated aromatic hydrocarbons and common tern egg extracts.

Experiments were conducted to compare the sensitivity ofprimary cultures of common tern (Sterna hirundo) and chicken(Gallus domesticus) embryo hepatocytes to cytochrome P4501A (CYP1A)induction and porphyrin accumulation after exposure to halogenated aromatichydrocarbons (HAHs) or tern egg extracts. The HAHs tested were2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD),2,3,7, 8-tetrachlorodibenzofuran (TCDF) 3,3',4,4'-tetrachlorobiphenyl (PCB 77;IUPAC nomenclature), 3,3',4,4',5-pentachlorobiphenyl (PCB 126),3, 3',4,4',5,5'-hexachlorobiphenyl (PCB 169) and Aroclor(R) 1254 (a commercialmixture of PCBs). Extracts were prepared from common tern eggs collected fromthree sites in the Great Lakes basin and one reference site on the east coastof Canada. CYP1A induction was assayed asethoxyresorufin-O-deethylase (EROD) activity and/or immunodetectableCYP1A protein, and total intracellular porphyrin accumulation was measuredfluorometrically. Unlike chicken embryo hepatocyte (CEH) cultures, nointracellular porphyrin accumulation was observed after treatment of ternembryo hepatocyte (TEH) cultures with HAHs or egg extracts. TEH cultures were approximately 50 to >1600 times less sensitive than CEH cultures to HAH-mediated CYP1Ainduction. In contrast, TEH cultures were either approximately equallysensitive or only 3.5-15 times less sensitive than CEH cultures to CYP1Ainduction mediated by tern egg extracts. These data suggest that common ternembryos may be more susceptible to the CYP1A inducing effects mediated bycomplex mixtures of environmental contaminants than indicated by theirresponse to individual HAHs.

Animals↗
PubMed1997

Raised concentration of serum bile acids following occupational exposure to halogenated solvents, 1,1,2-trichloro-1,2,2-trifluoroethane and trichloroethylene.

OBJECTIVES: The objectives of this study were threefold. First, to examine the hepatic effects of occupational exposure to 1,1,2-trichloro-1,2,2-trifluoroethane (FC 113) using conventional and newer tests (serum bile acids) of hepatobiliary function. Second, to assess the effects of altered work practices that included a reduced exposure to a different halogenated solvent (trichloroethylene) on the same parameters of liver function; and finally, to gather further data to support or refute the contention that serum bile acid (SBA) levels could provide a sensitive biological marker of exposure to these solvents. DESIGN: Two groups of workers (control and exposed) in an Australian steel industry participated in the study. The exposed group (n = 5-6) comprised individuals who had either exposure to FC 113 (68.2 +/- 12.6 ppm) or trichloroethylene (8.9 +/- 3.1 ppm) during the application of these solvents in a cleaning procedure, whereas the control group (n = 7-11) was composed of non-solvent-exposed office workers in the same company. The initial investigation involved exposure to FC 113 while a follow-up study was undertaken after changes in work practices were made including replacement of FC 113 with trichloroethylene (TRI). METHODS: Standard liver function tests and individual serum bile acids (ISBA) were measured before and after exposure to solvents and simultaneously in the control subjects by enzymatic methods and high performance liquid chromatography (HPLC), respectively. RESULTS: Statistical analysis of the data showed a significant increase in the concentration of total serum bile acids (TSBA), some of the subgroups of SBA, and a few of the ISBA in workers after a period of exposure to FC 113. After TRI replaced FC 113 together with other changes in work practices to give substantial reduction in exposure to solvent, a repeat study also found elevated SBA after the cleaning procedure but to a lesser extent. No other indications of adverse liver effects, as measured by conventional parameters of hepatobiliary function, were detected. CONCLUSION: Exposure to FC 113 was clearly associated with a significant rise in SBA levels, which are sensitive indicators of liver function. This finding is consistent with, and provides further support for, our previous investigations on chlorinated aliphatic hydrocarbon solvents which showed that SBA levels are a sensitive biological marker of exposure to these solvents. Changes in work practices including replacement of FC 113 resulted in a reduced effect on SBA, consistent with lower exposures.

Adult↗
PubMed1999

Inhibitory effect of nitric oxide on the metabolism of halogenated volatile anesthetics by cytochrome P-450.

PURPOSE: This study was undertaken to examine the effect of nitric oxide (NO) on the metabolism of halogenated volatile anesthetics (HVA) by cytochrome P-450 (CYP) under both aerobic and anaerobic conditions using rat hepatic microsomes. METHODS: A microsomal fraction was prepared by centrifugation from normal and phenobarbital-treated male SD rats. The anaerobic metabolism of HVA by CYP was followed by measuring the formation of a halothane CYP complex spectrophotometrically. Aerobic CYP activity was determined using either the defluorination of sevoflurane or the demethylation of aminopyrine. RESULTS: The formation of the halothane-CYP complex was dose-dependently inhibited by NO. NO also decreased CYP defluorination of halothane in a dose-dependent manner. In phenobarbital-induced microsomes, the inhibition rates of both complex formation and the defluorination of halothane were the same as those seen in normal microsomes. Although the defluorination of sevoflurane and the demethylation of aminopyrine were inhibited by NO aerobically, the inhibition was much less than that of the metabolism of halothane under anaerobic conditions. CONCLUSION: These results suggest that NO binds the heme of CYP and inhibits the metabolism of HVA, with the effect lasting for a prolonged period of time. Furthermore, the balance between NO and O(2) is important for NO to inhibit CYP.

Journal Article↗
PubMed2001

A new halogenated antidiabetic vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV): in vitro and in vivo insulinomimetic evaluations and metallokinetic analysis.

A new vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV), VO(IPA)2, with a VO(N2O2) coordination mode, was prepared by mixing 5-iodopicolinic acid and VOSO4 at pH 5, with the structure characterized by electronic absorption, IR, and EPR spectra. Introduction of the halogen atom on to the ligand enhanced the in vitro insulinomimetic activity (IC50 = 0.45 mM) compared with that of bis(picolinato)oxovanadium(IV) (IC50 = 0.59 mM). The hyperglycemia of streptozotocin-induced insulin-dependent diabetic rats was normalized when VO(IPA)2 was given by daily intraperitoneal injection. The normoglycemic effect continued for more than 14 days after the end of treatment. To understand the insulinomimetic action of VO(IPA)2, the organ distribution of vanadium and the blood disposition of vanadyl species were investigated. In diabetic rats treated with VO(IPA)2, vanadium was distributed in almost all tissues examined, especially in bone, indicating that the action of vanadium is not peripheral. Vanadyl concentrations in the blood of normal rats given VO(IPA)2 remain significantly higher and longer than those given other complexes because of its slower clearance rate. VO(IPA)2 binds with the membrane of erythrocytes, probably owing to its high hydrophobicity in addition to its binding with serum albumin. The longer residence of vanadyl species shows the higher normoglyceric effects of VO(IPA)2 among three complexes with the VO(N2O2) coordination mode. On the basis of these results, VO(IPA)2 is indicated to be a preferred agent to treat insulin-dependent diabetes mellitus in experimental animals.

Adipose Tissue↗
PubMed2004

Quantitative structure-activity relationships of mutagenic activity from quantum topological descriptors: triazenes and halogenated hydroxyfuranones (mutagen-X) derivatives.

The mutagenic activity of 23 triazenes and, in a different set, of 24 halogenated hydroxyfuranones (MX derivatives) is quantitatively related to new features of contemporary molecular wave functions. Nowadays affordable computers are powerful enough to rapidly generate geometry-optimised ab initio wave functions at HF/3-21G*, HF/6-31G* and B3LYP/6-311 + G(2d,p) level for all molecules. The bonds of a common molecular skeleton are described by their ab initio bond lengths and local properties provided by the theory of quantum chemical topology (QCT). The chemometric analysis involves two types: one to generate a statistically validated quantitative model, and one to isolate the active center. In the former a genetic algorithm (GA) selects bond descriptors in order to optimise the cross-validation error, q2, followed by a full partial least squares (PLS) analysis, which also yields randomisation statistics. In the latter type principal components (PCs) are constructed from the original bond descriptors and their variables important to the projection (VIPs) are plotted in a histogram. This analysis suggests a preferred mechanistic pathway for the initial hydroxylation of the triazenes, an issue that has remained ambiguous so far. In the case of the hydroxyfuranones the proposed method aids the elucidation of a mechanistic ambivalence.

Algorithms↗