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PubMed2004

Synthetic polymers adsorbing bisphenol A and its analogues prepared by covalent molecular imprinting using bisphenol A dimethacrylate as a template molecule.

Synthetic polymers which can adsorb bisphenol A (BPA) and related compounds were prepared by a covalent molecular imprinting technique. BPA dimethacrylate, used as template molecule, was polymerized with a crosslinker, triethylene glycol dimethacrylate (TEGDMA) or trimethylol propane trimethacrylate (TRIM). After the polymerization treatment with dilute NaOH was used to cleave BPA from the polymers. For high recovery of BPA with low polymer matrix degradation, the hydrolysis conditions were determined to be treatment with 1.0 mol L(-1) NaOH for 48 h. The binding sites generated by the hydrolysis were evaluated by determination of the retentivity of BPA, BPA analogues, and other endocrine disruptors. The polymers strongly adsorbed compounds with two hydroxyl groups at the 4,4'-positions. Generally the TEGDMA-based polymers had stronger affinity than the TRIM-based polymers, although the TRIM-based polymer adsorbed steroidal hormones with two hydroxyl groups, for example 17 alpha-estradiol and 17 beta-estradiol, more strongly than the TEGDMA-based polymer, meaning that the crosslinkers affected the properties of the binding sites and, depending upon the target molecules, suitable crosslinkers should be chosen in this system.

Adsorption↗

PubMed2002

Responses of L929 mouse fibroblasts, primary and immortalized bovine dental papilla-derived cell lines to dental resin components.

OBJECTIVE: The use of adequate target cells for cytotoxicity testing of dental restorative materials has often been experimentally assessed with respect to the clinical relevance of the test results. In the present study, the responses in primary bovine dental papilla-derived cells (pulp cells) were compared with those in transformed dental papilla-derived cell lines and L929 mouse fibroblasts after exposure to various dental resin compounds. METHODS: Primary bovine dental papilla-derived cells (CPC), tCPC B (CPC cells transformed with SV40 T-antigen), tCPC E (CPC cells transformed with E6/E7 oncogen), and L929 mouse fibroblast cells were exposed to various compounds of dental resin materials for 24 h, and cytotoxicity was determined using the MTT assay. Bis-GMA, UDMA, 1,6 hexane diol dimethacrylate (HDDM), TEGDMA, HEMA, MMA, camphorquinone (CQ), bisphenol A (BPA), and glycidyl methacrylate (GMA) were tested. Concentrations leading to 50% cell survival (TC50 values) were calculated from fitted dose-response curves. RESULTS: The simple ranking of the cytotoxic effects of the dental resin compounds in the four cell types was identical, and TC50 values determined in L929 cells here were consistent with findings by other authors using continuous cell lines. However, the concentrations of the resin compounds necessary for eliciting cytotoxic responses in the various cells were clearly different. The analyses of TC50 values of the resin compounds revealed a linear correlation between cell lines, and the overall sensitivities increased as follows: CPC=tCPC B<tCPC E<L929. SIGNIFICANCE: The low sensitivities of primary cells and transformed tCPC B cells compared with the continuous L929 cell line and the transformed tCPC E cells indicates the presence of specific structural and functional properties relevant in vivo. The differences between the transformed tCPC B and tCPC E cells may indicate modifications of cellular functions caused by the different transformation processes.

Acrylates↗

PubMed2001

Pharmacokinetics of tolterodine, a muscarinic receptor antagonist, in mouse, rat and dog. Interspecies relationship comparing with human pharmacokinetics.

Tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5) is an antimuscarinic agent developed specifically for the treatment of the overactive bladder. In this study, the pharmacokinetics of tolterodine were investigated in the mouse, rat and dog, following which allometric scaling was performed to predict oral pharmacokinetics in man. The intestinal absorption of tolterodine after oral dosing was almost complete in all three species, with peak serum concentrations observed within 1 hour post-dose. Bioavailability varied between 2-20% in rodents and 58-63% in the dog. A high volume of distribution in all three species was consistent with extravascular distribution. Tolterodine was extensively metabolised in all the animal models, but the profile of metabolism differed in the rat compared to the mouse and dog, the latter having similar metabolism routes as man. Limitation of metabolism capacity caused a non-linear increase of tolterodine concentrations with dose (repeat-dose study in the mouse), and changed the relative metabolite concentration pattern. The results suggest that the hydroxylation of tolterodine is a high affinity, low capacity pathway, while N-dealkylation follows a low affinity, high capacity pathway. The elimination of tolterodine from serum was rapid, with a half-life of less than 2 h in all species. A very high clearance in the mouse and rat (10-15 l/h.kg), and in the dog (1.4 l/h.kg), indicated additional non-metabolic clearance mechanisms for tolterodine (shown to be attributed to biliary excretion). Urinary excretion of compound-related radioactive substance was around 15%, 45% and 50%, respectively, in the rat, mouse and dog. Allometric scaling allowed a good prediction of clearance and volume of distribution to be extrapolated for comparison with tolterodine pharmacokinetics in man. In conclusion, the pharmacokinetics of tolterodine are similar in the mouse and dog, and correlate with that in man. Although the rat has a different metabolic profile, clearance fits into the allometric relationship between species, enabling prediction of total clearance of tolterodine in man from preclinical data.

Animals↗

PubMed1984

The sensitizing potential of di-(meth)acrylates based on bisphenol A or epoxy resin in the guinea pig.

Most composite materials in dentistry used today, contain resins based on dimethacrylates. BIS-GMA [2,2-bis-(4-(2-hydroxy-3-methacryloxypropoxy)phenyl)propane], the addition reaction product of bisphenol A and glycidyl methacrylate or an epoxy resin and methacrylic acid, is used most extensively. More recently, dimethacrylates based on bisphenol A, with various chain lengths have appeared on the market as a substitute for or in addition to BIS-GMA. Such compounds are BIS-MA [2,2-bis-(4-(methacryloxy)phenyl)propane], BIS-EMA [2,2-bis-(4-(2-methacryloxyethoxy)phenyl)propane] and BIS-PMA [2,2-bis-(4-(3-methacryloxypropoxy)phenyl)propane]. Increasing interest in the radiaton cure of coatings and printing inks have focused attention on these substances and on epoxy diacrylates as radiation-curable resins. The sensitizing capacity of the different acrylates based on bisphenol A or epoxy resin have been investigated with the guinea pig maximization test. The pattern of simultaneous reactivity of the compounds was also studied. Epoxy diacrylate [2,2-bis-(4-(2-hydroxy-3-acryloxy-propoxy)phenyl)propane], BIS-EMA and BIS-MA are shown to be strong sensitizers, while the linear fraction of BIS-GMA and its isomers and BIS-PMA have none or a low sensitizing capacity. The impurities in the BIS-GMA and BIS-MA batches seem to have high allergenic potential. These results stress the importance of a pure substance when discussing allergenicity and cross reactions.

Acrylates↗

PubMed2006

Biological assessment of bisphenol A degradation in water following direct photolysis and UV advanced oxidation.

Endocrine disrupting compounds (EDCs) are exogenous environmental chemicals that can interfere with normal hormone function and present a potential threat to both environmental and human health. The fate, distribution and degradation of EDCs is a subject of considerable investigation. To date, several studies have demonstrated that conventional water treatment processes are ineffective for removal of most EDCs and in some instances produce multiple unknown transformation products. In this study we have investigated the use of direct photolysis with low-pressure (LP) Hg UV lamps and UV+hydrogen peroxide (H(2)O(2)) advanced oxidation process (AOP) for the degradation of a prototypic endocrine disrupter, bisphenol A (BPA), in laboratory water. Removal rates of BPA and formation of degradation products were determined by high performance liquid chromatography (HPLC) analysis. Changes in estrogenic activity were evaluated using both in vitro yeast estrogen screen (YES) and in vivo vitellogenin (VTG) assays with Japanese medaka fish (Oryzias latipes). Our results demonstrate that UV alone did not effectively degrade BPA. However, UV in combination with H(2)O(2) significantly removed BPA parent compound and aqueous estrogenic activity in vitro and in vivo. Removal rates of in vivo estrogenic activity were significantly lower than those observed in vitro, demonstrating differential sensitivities of these bioassays and that certain UV/AOP metabolites may retain estrogenic activity. Furthermore, the UV/H(2)O(2) AOP was effective for reducing larval lethality in treated BPA solutions, suggesting BPA degradation occurred and that the degradation process did not result in the production of acutely toxic intermediates.

Animals↗

PubMed2005

The C3a receptor antagonist SB 290157 has agonist activity.

The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-Galpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.

Animals↗

PubMed2004

The induction of gene mutations and micronuclei by oxiranes and siloranes in mammalian cells in vitro.

Oxiranes and siloranes are candidate molecules for the development of composite materials with low shrinkage. Since some of these molecules are highly reactive, they could lead to adverse biological effects from underlying genetic mechanisms. Therefore, we analyzed the formation of micronuclei (chromosomal aberrations) and the induction of gene mutations (HPRT assay) in mammalian cells. The numbers of micronuclei induced by the oxirane di(cyclohexene-epoxidemethyl)ether (Eth-Ep) at low concentrations (10 micro M) were about five-fold higher than controls. The related compound epoxy cyclohexyl methyl-epoxy cyclo-hexane carboxylate (Est-Ep) was less effective. The activity of diglycidylether of bisphenol A (BADGE) was even lower but similar to the most reactive silorane, di-3,4-epoxy cyclohexylmethyl-dimethyl-silane (DiMe-Sil). No induction of micronuclei was detected in the presence of a rat liver homogenate (S9). Est-Ep and Eth-Ep also induced gene mutations. Our analyses indicated low mutagenic potentials of siloranes; however, some oxiranes induced strong effects at two genetic endpoints.

Animals↗

PubMed2000

Detection of bisphenol-A in dental materials by gas chromatography-mass spectrometry.

The xenoestrogenic substance bisphenol-A is widely used as a synthetic precursor of resin monomers, such as bisphenol-A diglycidyl methacrylate. Reports describing the release of bisphenol-A from polymerized resin into saliva have aroused considerable concern regarding exposure to xenoestrogen by dental treatment. The purpose of the present study was to demonstrate a reliable methodology of detecting the trace amounts of bisphenol-A in dental materials. Bisphenol-A was separable from bisphenol-A diglycidyl methacrylate, which is often employed as the principal dimethacrylate monomer, by selective extraction with a Sep-Pak C18 cartridge. Using this extraction method in combination with a gas-chromatography mass-spectrometry, we have obtained evidence that all unpolymerized materials used in this study were contaminated with bisphenol-A. Quantitative analysis using a deuterium-labeled compound as an internal standard revealed bisphenol-A contents in commercial dental materials ranging from < 1 microgram/g material to about 20 micrograms/g material. The polymerized dental materials released up to 91.4 ng bisphenol-A/g material into phosphate buffered saline during 24-h incubation. These results indicate that bisphenol-A can be released from dental materials, however the leachable amount would be less than 1/1000 of the reported dose (2 micrograms/kg body weight/day) required for xenoestrogenisity in vivo.

Benzhydryl Compounds↗

PubMed1989

Differential effects of a new central adrenergic agonist--modafinil--and D-amphetamine on sleep and early morning behaviour in young healthy volunteers.

Modafinil (CRL 40476) is a recently developed central alpha adrenergic agonist with vigilance-promoting properties. In a double-blind, placebo-controlled sleep laboratory study, its single-dose effects on objectively and subjectively evaluated sleep, morning awakening, and early morning behaviour were investigated and compared with amphetamine. Ten young healthy volunteers of both sexes spent 12 nights in the sleep laboratory: one adaptation night, one baseline night, five drug nights (100 mg and 200 mg modafinil; 10 mg and 20 mg d-amphetamine; placebo) and five subsequent washout nights. The drugs were administered in one week intervals according to a Latin square design. Somnopolygraphic investigations were performed between 22h30 and 06h00. Subjects received the drug orally half an hour before bedtime. A self-rating scale for sleep and awakening quality and early morning behavior was completed subsequent to the morning toilet. Thereafter, noopsychic and thymopsychic variables were evaluated utilizing a psychometric test-battery. Statistical analyses of objective sleep variables demonstrated that modafinil causes no significant changes as compared to a placebo. Sleep initiation remained unchanged after all of the drugs, while sleep maintenance was impaired dose-dependently after d-amphetamine. Thus, total sleep time and sleep efficiency decreased significantly after 20 mg d-amphetamine as compared to the placebo and modafinil. In regard to sleep architecture a reduction of sleep stage 2 and rapid eye movement-sleep occurred under d-amphetamine while modafinil did not exhibit such an effect. Subjective sleep quality was significantly better after modafinil than after the reference compound. Subjective awakening quality and well-being in the morning did not show any significant findings. Furthermore, no differences were observed between the placebo and the other drugs concerning objective awakening quality (evaluated by psychometric tests). Critical flicker frequency increased significantly after 20 mg d-amphetamine as compared to the placebo. Pulse rate and evening and morning blood pressure remained unchanged. These data stress the necessity to differentiate between "vigility-increasing" properties of amphetamine and "vigilance-promoting" properties of modafinil.

Adult↗

PubMed2004

Identification of diphenhydramine metabolites in human urine by capillary electrophoresis-ion trap-mass spectrometry.

The identification of diphenhydramine (DH) metabolites that are frequently observed in the capillary zone electrophoresis (CZE) and micellar electrokinetic capillary chromatography (MEKC) analyses of alkaline liquid/liquid and solid-phase extracts of patient urines is demonstrated. Having standards for DH and diphenhydramine-N-oxide (DHNO), the presence of these two compounds could be confirmed in urines that were collected overnight after administration of 25 mg DH chloride. Using CZE coupled to ion-trap mass spectrometry (CE-MS(n)) with positive electrospray ionization and an acetate buffer at pH 5.6, the [M+H](+) ions of DH (m/z = 256), DHNO (m/z = 272), and nordiphenhydramine (NDH, m/z = 242) and their fragmentation to a common m/z 167 product ion (diphenylcarbinol moiety) was monitored. The data indicate that all three compounds are cations in an acidic environment, the migration order being NDH, DH, and DHNO. Data obtained under negative electrospray ionization conditions suggest the presence of diphenylmethoxyacetic acid-glycine amide ([M-H](-) ion of m/z 298 and fragmentation to m/z 254, loss of CO(2)), a metabolite that could tentatively be assigned to a characteristic peak observed in the MEKC electropherogram at alkaline pH. The data presented in this paper illustrate the value of using CE-MS(n) for identification of urinary drug metabolites for which no standards are available.

Acetates↗

PubMed2005

Simultaneous determination of tetrabromobisphenol A, tetrachlorobisphenol A, bisphenol A and other halogenated analogues in sediment and sludge by high performance liquid chromatography-electrospray tandem mass spectrometry.

A high performance liquid chromatography-electrospray (negative) ionization-tandem mass spectrometry (HPLC-ESI(-)-MS-MS) based method has been developed for simultaneous determination of bisphenol A (BPA), tetrachlorobisphenol A (TCBPA), and tetrabromobisphenol A (TBBPA), as well as lower brominated BPA analogues in sediment and sludge samples. Samples were extracted with MTBE, target compounds were partitioned by aqueous solution of sodium hydroxide. The solution was subsequently acidified, and the enrichment and desalting were performed via solid phase extraction (SPE). After cleanup the target compounds were determined by HPLC-ESI(-)-MS-MS. The method limits of quantification (MLOQs) from sediment and sludge for BPA, monobromo-bisphenol A (mono-BBPA), dibromo-bisphenol A (di-BBPA), tribromo-bisphenol A (tri-BBPA), TBBPA and TCBPA were 0.15, 0.02, 0.02, 0.04, 0.05, and 0.03 ng/g (dry weight), respectively. Mean recovery of the analytes from spiked samples ranged from 70 to 105%, and the relative standard deviation ranged from 4.9 to 13.1%. The method was successfully applied to sediment and sludge samples analysis.

Benzhydryl Compounds↗

PubMed1997

'Wide-spectrum Ca2+ channel antagonists': lipophilicity, inhibition, and recovery of secretion in chromaffin cells.

Repetitive application of short depolarizing K+ pulses (70 mM K+, 2 mM Ca2+ Krebs-HEPES solution, for 10 s every 5 min) produced reproducible catecholamine secretory responses from superfused bovine chromaffin cells. At 10 microM for 15 min, the piperazine derivatives dotarizine, flunarizine and lidoflazine inhibited secretion by around 90%; cinnarizine halved the secretory response. Recovery of secretion after 30-min washout with Krebs-HEPES solution amounted to 75% in the case of dotarizine, 8% for flunarizine, 46% for lidoflazine and 21% for cinnarizine. The benzothiazol derivatives (10 microM) (+)-S-lubeluzole and R91154 (the (-)-R-enantiomer of lubeluzole) blocked the response by 75%; sabeluzole inhibited secretion by only 34% and R56865 (N-[1-(4-(4-fluorophenoxy)butyl]-4-piperidinyl-N-methyl-2-benzo-thiaz olamine) by 61%. Recoveries were around 70% in the case of these four benzothiazol derivatives. The diphenylbutyl-piperazine derivatives fluspirilene and penfluridol inhibited secretion by over 80%; no recovery was produced after 30-min washout. The inhibition of secretion was time dependent, as the recovery of the response was. Blockade of secretion by dotarizine and flunarizine occurred even in the absence of intermittent K+ stimulations of the cells. No obvious correlation was seen between the octanol/water partition coefficients of the ten compounds tested (that ranged between 6 and 4.61), the rate and extent of blockade of secretion, and the recovery of the secretory response upon washout. Rather than non-specific actions on ion channels (and secretion) due to their high lipophilicity, we believe that blockade of various Ca2+ channels relates to their binding properties to specific channel micro and macrodomains, as the case might be for 'narrow' (omega-conotoxin GVIA) and 'wide-spectrum' (omega-conotoxin MVIIC) peptide toxins.

Animals↗

PubMed1998

Selective muscarinic antagonists. I. Synthesis and antimuscarinic properties of 4-piperidyl benzhydrylcarbamate derivatives.

A series of 1-substituted-4-piperidyl benzhydrylcarbamate derivatives were synthesized and evaluated for binding affinity to M1, M2 and M3 receptors, and for antimuscarinic activities. Receptor binding assays indicated that 1-benzyl-4-piperidyl benzhydrylcarbamate derivatives showed higher affinities for M1 and M3 receptors, and good selectivities for M3 over M2 receptor, than the corresponding ester analog. These results indicate that the urethane bond is a novel linker for muscarinic antagonists, and serves to lock the molecular conformation and allows the hydrophobic portion and cationic site of the molecule to bind to M1 and M3 muscarinic receptors. Among the prepared compounds, 1-(4-methylaminobenzyl)-4-piperidyl benzhydrylcarbamate monohydrochloride (18b, YM-58790) exhibited potent inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, comparable to oxybutynin and was approximately ten times less inhibitory on oxotremorine-induced salivary secretion than oxybutynin in rats. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, demonstrated that YM-58790 can be useful for treatment of urinary urge incontinence as a bladder-selective M3 antagonist with fewer side effects.

Animals↗

PubMed1982

Synthesis of terfenadine.

The synthesis of alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) is described. A limited structure-activity analysis of the central nervous system-mediated side effects of this compound and related analogs is made relative to the antipsychotic agent, haloperidol. Modification of the piperidine 4-position substituents of haloperidol to give a 4-(alpha, alpha-diphenylmethanol) moiety has conveyed histamine H1 -antagonism to the anti-psychotic agent, haloperidol. Structural changes of this fluorobutyrophenone have progressively reduced and finally eliminated centrally-mediated side effects. The result of this exercise is terfenadine, a preferred antihistamine, potent and selective in antagonizing histamine H1-receptor-mediated responses but lacking the usual side effect profile of known histamine H1-receptor antagonists.

Animals↗

PubMed1993

Positive- and negative-ion mass spectrometry of diphenylmethane antihistaminics and their analogues and rapid clean-up of them from biological samples.

Positive-ion electron impact (PIEI), positive-ion chemical ionization (PICI) and negative-ion chemical ionization (NICI) mass spectra are presented for 15 compounds of diphenylmethane antihistaminics and their analogues, and each fragmentation pathway was analyzed. In the PIEI mode, molecular peaks were very small or missing for most compounds. Peaks at m/z 58, due to a dimethylaminomethyl group liberated, constituted base peaks in five compounds. Peaks at m/z 165 and/or 167, due to diaromatic rings plus a methyl group, appeared in most compounds. In the PICI mode, peaks due to M+H and M+C2H5 appeared in all compounds. Peaks due to diaromatic rings plus a methyl or ethyl group constituted base peaks in five compounds, which had an ether bond in their structures. In the NICI mode, anions at m/z M-H appeared in most compounds. Peaks at m/z 35 were observed for compounds having a chlorine group in their structures. Detection limits for total ion monitoring of these compounds were 20-50 ng on column in the PIEI mode, 100-200 ng in the PICI mode and 500-1000 ng in the NICI mode. A rapid and simple clean-up procedure of these drugs with use of Sep-Pak C18 cartridges is also presented. The drugs could be detected by gas chromatography with DB-1 and DB-17 capillary columns with satisfactory separation from impurities in their underivatized forms. The recovery of the drugs, which had been added to whole blood and urine, was more than 60% except for meclizine.

Benzhydryl Compounds↗

PubMed2003

Competitive interactions of chlorinated phenol compounds with 3,3',5-triiodothyronine binding to transthyretin: detection of possible thyroid-disrupting chemicals in environmental waste water.

Chlorinated phenol compounds, such as the chlorinated derivatives of bisphenol A, have been detected in effluents from paper manufacturing plants. We investigated the effects of bisphenol A, nonylphenol, and their seven chlorinated derivatives on 3,3',5-[(125)I]triiodothyronine ([(125)I]T(3)) binding to purified chicken and bullfrog transthyretin (cTTR and bTTR) and to the ligand-binding domains of chicken and bullfrog thyroid hormone receptor beta (cTR LBD and bTR LBD). The concentrations at which the chlorinated derivatives displaced [(125)I]T(3) from TTR were 10-10(3) times less than those of their parent molecules. 2,6-Dichloro-4-nonylphenol and 3,3',5-trichlorobisphenol A were the most potent competitors of T(3) binding to cTTR and to bTTR, respectively. The interactions of the chlorinated derivatives with the cTR and the bTR LBDs were weaker than those of the chlorinated derivatives with cTTR and bTTR. Chlorinated derivatives with a greater degree of chlorination were more efficient competitors of T(3) binding to TTR and TR. A structure-activity relationship between the phenol compounds and TTR (TTR assay) and TR (TR assay) was established. Structures with chlorine in either ortho position or both ortho positions, with respect to the hydroxy group, were more efficient competitors. Chemicals that interacted with bTTR, cTTR, and Japanese quail TTR were detected in water downstream of effluents from paper manufacturing plants using the TTR assay. As some of the chlorinated bisphenols and nonylphenols were potent competitors of T(3) binding to TTRs, the TTR assay could be applied as primary screening for possible thyroid-disrupting chemicals in environmental waste water.

Animals↗

PubMed1998

Biotransformation of the major fungal metabolite 3,5-dichloro- p-anisyl alcohol under anaerobic conditions and its role in formation of Bis(3,5-dichloro-4-Hydroxyphenyl)methane.

Higher fungi have a widespread capacity for biosynthesis of organohalogens. Commonly occurring chloroaromatic fungal metabolites can end up in anaerobic microniches at the boundary of fungal colonies and wetland soils. The aim of this study was to investigate the environmental fate of a major fungal metabolite, 3, 5-dichloro-p-anisyl alcohol, under anaerobic conditions. This compound was incubated with methanogenic sludge to study its biotransformation reactions. Initially, 3,5-dichloro-p-anisyl alcohol was readily demethylated in stoichiometric quantities to 3, 5-dichloro-4-hydroxybenzyl alcohol. The demethylated product was converted further via two routes: a biotic route leading to the formation of 3,5-dichloro-4-hydroxybenzoate and 2,6-dichlorophenol, as well as an abiotic route leading to the formation of bis(3, 5-dichloro-4-hydroxyphenyl)methane. In the first route, the benzyl alcohol moiety on the aromatic ring was oxidized, giving 3, 5-dichloro-4-hydroxybenzoate as a transient or accumulating product, depending on the type of methanogenic sludge used. In sludge previously adapted to low-molecular-weight lignin from straw, a part of the 3,5-dichloro-4-hydroxybenzoate was decarboxylated, yielding detectable levels of 2,6-dichlorophenol. In the second route, 3, 5-dichloro-4-hydroxybenzyl alcohol dimerized, leading to the formation of a tetrachlorinated bisphenolic compound, which was identified as bis(3,5-dichloro-4-hydroxyphenyl)methane. Since formation of this dimer was also observed in incubations with autoclaved sludge spiked with 3,5-dichloro-4-hydroxybenzyl alcohol, it was concluded that its formation was due to an abiotic process. However, demethylation of the fungal metabolite by biological processes was a prerequisite for dimerization. The most probable reaction mechanism leading to the formation of the tetrachlorinated dimer in the absence of oxygen is presented, and the possible environmental implications of its natural occurrence are discussed.

Anaerobiosis↗

PubMedDate not supplied

Irreversible binding to proteins after single and repeated daily oral administration of 4-(2,2-diphenylethyl) imidazole (SC-46264) to the Cynomolgus monkey.

SC-46264 is an antagonist of the alpha 2-adrenergic receptor. Distribution and excretion of [14C]-SC-46264 were studied after single and repeated daily oral administrations to the Cynomolgus monkey at a 1.5 mg/kg dose. After a single oral administration, more than 95% of the administered dose was recovered within 48 h in the urine (+/- 60%) and faeces (+/- 40%). Approximately 1.7% remained in the gastro-intestinal (GI) tract and 2% in the animal body. However, the radioactivity remaining in the animal body decreased very slowly from 2 to 1% between 48 and 144 h. An accumulation of very small amounts of radioactivity could be suspected in the plasma, the liver, the thyroid, the adrenals and the kidneys. In a 2 week daily oral administration of [14C]-SC-46264, the amount of total radioactivity remaining in the animal body 24, 48 and 216 h after the last administration was approximately 21, 11 and 5% of the daily administered dose, respectively. It confirmed the accumulation of [14C]-SC-46264 related compound in the plasma, the liver, the thyroid, the adrenals and the kidneys. The minimum plasma concentrations of total radioactivity observed before each administration increased during the treatment and apparently did not yet reach an equilibrium after 14 days. In these plasma samples obtained throughout the study, an increasing fraction of the total radioactivity could not be extracted and was recovered with precipitable material. These observations lead to the hypothesis of an irreversible binding of some material to the proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗