Hepatic microsomal metabolism of the dichloroethanes

The binding of 1,1-dichloroethane (1,1-DCE) to the substrate binding site of hepatic microsomal cytochrome P-450, and the stimulation of hepatic microsomal CO-inhibitable NADPH oxidation by 1,1-DCE and 1,2-dichloroethane (1,2-DCE) were enhanced by induction with phenobarbital but not with beta-naphthoflavone. Incubation of the dichloroethanes with hepatic microsomes from phenobarbital-treated rats, NADPH-generating system and EDTA resulted in the conversion of 1,1-DCE to acetic acid and to a lesser extent to 2,2-dichloroethanol and probably also mono- and dichloroacetic acid and the conversion of 1,2-DCE to chloroacetaldehyde and to a lesser extent to chloroacetic acid and probably 2-chloroethanol. In addition, reaction mixtures constituted as described above resulted in slight but significant losses (ca. 13%) of hepatic microsomal cytochrome P-450. The omission of dichloroethane or the NADPH-generating system from incubation mixtures eliminated the above effects, and SKF-525A or CO diminished or eliminated the effects. Pathways for the metabolism of 1,1-DCE and 1,2-DCE are proposed.     

Interaction between 1,2-Dichloroethane and Disulfiram: I. Toxicologic Effects

Interaction between 1,2-Dichioroethane and Disulfiram. 1. ToxicologicEffects. IGWE, O. J., QUE HEE, S. S., AND WAGNER, W. D. (1986).Fundam Appl. Toxicol. 6, 733–746. Inhalation and intraperitoneal(ip) studies with 1,2-dichloroethane (1,2-DCE) using Sprague-Dawleyrats fed 0.15% disulfiram (tetraethylthiuram disulfide; Antabuse;DSF) in AIN-76 diet [approx. (79 ± 11) mg DSF/kg bodywt/day] resulted in the observation of a toxic interaction relativeto either agent alone. The combination treatment caused testicularatrophy and histopathology in the liver and testes at 1,2-DCEinhalation concentrations >300 ppm (an estimated dose of194 mg/kg body wt/day) administered 5 days/week for 30 daysor at ip doses of 150 mg 1,2-DCE/kg body wt/day over 30 days,7 days/week. DSF lowered the 1,2-DCE dose at which liver enlargement,decreased liver/body weight ratios, and decreased body weightgains appeared relative to exposure to the 1,2-DCE alone. Forthe ip study, a decrease in spleen weight also occurred. Testicularatrophy and liver pathology had previously been observed inrats exposed to 20 ppm of ethylene dibromide (EDB) and fed 0.05%DSF in rat chow diet; EDB or DSF alone did not elicit testicularatrophy. These toxic effects indicate that 1,2-DCE may interactwith DSF as does EDB, but at a much higher dose.     

Cytotoxicity of halogenated alkanes in primary cultures of rat hepatocytes from normal, partial hepatectomized, and preneoplastic/neoplastic liver

Six halogenated hydrocarbons, chloroform, 1,2-dibromoethane (1,2-DBE), 1,1-dichloroethane (1,1-DCE), 1,2-dichloroethane (1,2-DCE), 1,1,1-trichloroethane (1,1,1-TCE), and 1,1,2-trichloroethane (1,1,2-TCE), were evaluated for their cytotoxicity in primary cultures of rat hepatocytes isolated from normal, partially hepatectomized, and preneoplastic/neoplastic rat livers. Preneoplastic/neoplastic lesions of phenotypically altered foci and hepatocyte nodules were induced by either (1) initiation by diethylnitrosamine (DENA) followed by 2 weeks of 0.02% 2-acetylaminofluorene (2-AAF) in the diet and a single gavage dose of carbon tetrachloride 1 week after the start of the 2-AAF diet or (2) initiation by DENA followed by promotion with 500 ppm sodium phenobarbital in the drinking water for 24 weeks. The hepatocytes containing preneoplastic/neoplastic cells isolated from animals treated with either protocol, compared to hepatocytes isolated from normal liver, were resistant to the cytotoxicity of aflatoxin B1 (AFB1). None of the six halogenated alkanes exhibited any difference in their cytotoxicity toward hepatocytes isolated from normal liver or from liver containing preneoplastic/neoplastic lesions induced by either procedure. Hepatocytes isolated from partially hepatectomized animals were resistant to the cytotoxicity of AFB1 and chloroform but not to the cytotoxicity of 1,2-DBE or 1,2-DCE. The ranking of relative cytotoxicity in hepatocytes from untreated rats was 1,2-DBE much greater than 1,2-DCE greater than 1,1,2-TCE greater than 1,1,1-TCE greater than chloroform greater than 1,1-DCE. Treatment with SKF-525A protected the hepatocytes from the cytotoxicity of AFB1 while increasing the cytotoxicity of all six halogenated alkanes. Treatment with diethyl maleate increased the cytotoxicity of AFB1 and all six halogenated alkanes. These observations suggest that preneoplastic/neoplastic rat hepatocytes are not resistant to the cytotoxicity of the six halogenated alkanes because their toxicity might be mediated by a cytochrome P-450 species which is not inhibited by SKF-525A and is not decreased in preneoplastic/neoplastic lesions.     

Slower dissolution rates of sulphamerazine in aqueous sodium dodecyl sulphate solutions than in water

The solubility of sulphamerazine in 0.1 M sodium dodecyl sulphate solution (SDS) was found to be 2.8-times that in water (at standard reporting conditions). The thermodynamics of transfer to the micelle were indicative of a spontaneous, enthalpy-driven, process. Contact angle and surface energy data revealed a favoured interaction between drug and SDS micelles, however, the dissolution rate of the drug into SDS decreased with increasing SDS concentration. The activation thermodynamics revealed a slight activation barrier to solubilisation. Apparent diffusion coefficients were calculated from initial dissolution rates from rotating disks, with different rotating speeds. The greatly reduced diffusion coefficient in the presence of micelles was taken as an explanation for the reduced rate of dissolution. The changes in solubility and diffusion rate have been considered in terms of the Noyes-Whitney equation, to show the combined effect on dissolution rate is as seen, i.e., reduced dissolution rate, despite the increased solubility. Care should be taken before assuming that an SDS solution is an appropriate medium for improving dissolution test data for poorly soluble drugs.     

Kinetic characterization of CYP2E1 inhibition in vivo and in vitro by the chloroethylenes

Trans- and cis-1,2-dichloroethylene (DCE) isomers inhibit their own metabolism in vivo by inactivation of the metabolizing enzyme, presumably the cytochrome P450 isoform, CYP2E1. In this study, we examined cytochrome P450 isoform-specific inhibition by three chloroethylenes, cis-DCE, trans-DCE, and trichloroethylene (TCE), and evaluated several kinetic mechanisms of enzyme inhibition with physiological models of inhibition. Trans-DCE was more potent than cis-DCE, and both were much more effective than TCE in inhibiting CYP2E1. The kinetics of in vitro loss of p-nitrophenol hydroxylase (pNP-OH) activity (a marker of CYP2E1) in microsomal incubations and of the in vivo gas uptake results were most consistent with a mechanism in which inhibition of the metabolizing enzyme (CYP2E1) was presumed to be related to interaction of a reactive DCE metabolite with remaining substrate-bound, active CYP2E1. The kinetics of inhibition by TCE, a weak inhibitor in vitro, were very different from that of the dichloroethylenes. With TCE, parent compound concentrations influenced enzyme loss. Trans-DCE was a more potent inhibitor of CYP2E1 than cis-DCE based on both in vivo and in vitro studies. Quantitative differences in the inhibitory properties of the 1,2-DCE isomers may be due to the different stability of epoxides formed from bioactivation by CYP2E1. Epoxide intermediates of DCE metabolism, reacting by water addition, would yield dialdehyde, a potent cross-linking reagent. Received: 6 October 1997 / Accepted: 24 March 1998     

The influence of gel formulation on the diffusion of salicylic acid in polyHEMA hydrogels

The influence of solute concentration, gel hydration, and crosslinking density on diffusion rates in polyHEMA hydrogels has been investigated using a radio-tracer technique. At hydrations above 31% water, diffusion is by pore flow, and increases in the crosslinking density of gels bring about a decrease in the diffusion coefficient, D. Below 31% hydration, diffusion is predominantly by solution diffusion and changes in crosslinking density have little effect on the diffusion coefficient. The diffusion coefficient is invariant with solute concentration within the range reported, although at a very high solute concentration, for the gels of lower hydration, the diffusion coefficient is higher than expected. A high value for D may be due to saturation of the binding sites of the diffusant on the polymer chains, leaving a greater proportion of diffusant available for transport.     

The effect of salts on the micellization temperature of aqueous poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) solutions and the dissolution rate and water diffusion coefficient in their corresponding gels.

Studies were performed to examine the effect of ionic salts on phase transitions, dissolution rates, and diffusion coefficients of water in gels of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) with polymer concentrations ranging from 22 to 32% w/w and salt concentrations ranging from 0 to 1.5% w/w. Salts tested include Na(3)PO(4), Na(2)SO(4), Na(2)HPO(4), NaH(2)PO(4), NaCH(3)CO(2), NaCl, and KI. Micellization transition temperatures were obtained using differential scanning calorimetry. The dissolution rates were obtained by measurement of the surface erosion rates, and diffusion coefficients were obtained by using a method to analyze the intrusion of water into the aqueous gels. It was found that salts had no effect on the dissolution rate of the polymer gels into deionized water. However, when the salt concentration in the aqueous dissolution media was adjusted to match the concentration in the gels, the dissolution rate of the polymer gel decreased with increasing salt concentration. The salts also had a profound effect on the critical micellization temperature (CMT) and the diffusion coefficient of water within the gel. The diffusion coefficient and CMT decreased in the presence of salts. The magnitude of these effects was comparable to their placement on the Hofmeister, or lyotropic series for salts. The effects of polymer and salt concentrations on the CMT were quantified, and a single correlation was proposed to predict the micellization temperatures for a wide range of salt and polymer concentrations.     

SDS-aided immobilization and controlled release of camptothecin from agarose hydrogel.

Camptothecin (CPT), known to be an effective anticancer drug, has a limited therapeutic utility because of its poor water solubility. In this work, an approach has been made to overcome the limitation. CPT was first incorporated into the micelles formed from an ionic surfactant, sodium dodecyl sulfate (SDS) and the micellar drug aqueous solution was then used in preparation of the agarose hydrogel. It has been found that the presence of SDS greatly increased the solubility of CPT in water. For example, in 1 ml of 1.0 wt.% SDS water solution, 0.11 mg CPT could be solubilized (0.318 mM), which was 83 times the solubility in pure water. It was the hydrophobic cores of the SDS micelles that were able to accept the lipophilic drug to form stable drug-immobilized micelles. The formulation of a hydrogel using the drug-immobilized micelles has allowed us to obtain a unique and novel drug release system where the drug molecules are encapsulated by the micelles and the drug-containing micelles are dispersed in the gel network. The release of CPT from the so deliberately fabricated agarose hydrogel system has been studied as a function of surfactant concentration at 37 degrees C. The diffusion coefficients of CPT obtained by fitting to Fick's law ranged from 2.12 to 7.36 x 10(-7)cm(2)s(-1). The results showed that SDS prolonged the drug release by reducing the diffusion coefficient of CPT in the gel.     

Magnetic resonance imaging study of the transport phenomena of solvent into the gel layer of hypromellose matrices containing tetracycline hydrochloride

Magnetic resonance imaging was used to study the diffusion of a water solution of hydrochloric acid into hypromellose (hydroxypropylmethylcellulose) matrices. Spatially resolved information was obtained about the self-diffusion coefficient and spin-spin relaxation time of solvent protons in the gel layer of hypromellose matrices loaded with different amounts of tetracycline hydrochloride. The data showed the influence of the drug concentration on the diffusion and spin-spin relaxation. Higher drug concentrations in the hypromellose matrix led to greater swelling of the matrix and faster diffusion of the water molecules inside the gel layer of the polymer. The observed differences between the radial and axial diffusion were interpreted in terms of the stresses imposed in the axial direction during the compression of the samples. The spin-spin and diffusion profiles indicated that the diffusion of a water solution of hydrochloric acid into hypromellose, pure and loaded with different amounts of tetracycline hydrochloride, was characterized as a Case II mechanism.     

Terpenes increase the partitioning and molecular dynamics of an amphipathic spin label in stratum corneum membranes

In this work, the interaction of the skin penetration enhancers dl-menthol, -terpineol, 1,8-cineole and (+)-limonene with the uppermost skin layer, the stratum corneum and with multilamellar vesicles from 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) is investigated by electron paramagnetic resonance (EPR) spectroscopy of the small spin label 2,2,6,6,-tetramethylpiperedine-1-oxyl (TEMPO), which partitions the aqueous and hydrocarbon phases. The EPR spectrum allows for the determination of the actual partition coefficient and the rotational diffusion rates of the spin probe in the two environments. The enthalpy changes, ΔH°, to transfer the spin probe from the aqueous to the hydrocarbon phase, as well as the activation energies associated to its rotational motion, were considerably smaller for stratum corneum, indicating less pronounced thermal reorganization. For DPPC, the terpenes increased both the partition coefficient and the rotational diffusion rate of the spin label in the membrane, except in the liquid–crystalline phase, while these increases in stratum corneum were observed in the entire temperature range measured with the exception of the rotational motion parameter for dl-menthol and -terpineol at temperatures below their melting point (32–41 °C). It is suggested that the terpenes effectively acting as spacers in the membrane fluidize the lipids and cause ruptures in the hydrogen-bonded network of the polar interface.     

乙酰螺旋霉素的液/液界面电化学研究

目的：研究乙酰螺旋霉素的液／液界面转移电化学特性。方法：利用循环伏安法记录乙酰螺旋霉素在水／硝基苯界面转移的循环伏安曲线,计算转移过程的热力学常数。结果：乙酰螺旋霉素在pH2-9范围通过水／硝基苯界面转移,标准转移电位为162mv,标准转移自由能为－1．5KJ/mol。结论：乙酰螺旋霉素的液／液界面转移过程为扩散控制的可逆过程。研究结果有助于对乙酰螺旋霉素的药理和药效的深入认识。     

Characterization of the drug release process by investigation of its temperature dependence

Temperature-dependent drug release from disintegrating tablets made of NaCl-containing agglomerated micronized cellulose (AMC) granules has been studied to characterize the release process. Release measurements on tablets compacted at three different compaction pressures; 50, 100, and 200 MPa, were performed at seven different temperatures; 6, 23, 33, 43, 50, 55, and 63 degrees C using the recently developed alternating ionic current method. Tablets compacted at different compaction pressures showed similar release rates. The release process was found to be diffusion-controlled, and the activation energy of the diffusion coefficient was comparable to that obtained for diffusion in pure water. The results show that the AMC granules in contact with water swell to a size and shape that is only slightly affected by their compaction history and the ion diffusion operates mainly within liquid-filled pores within the AMC granules. By using the temperature dependence of the release process, it was possible to reach this conclusion without any assumptions concerning the number and radii of the granules into which the tablets disintegrated. Further, the magnitude of the effective diffusion coefficient was found to be approximately 7.5 x 10(-10) cm(2)/s, which is approximately four orders of magnitude lower than for unhindered diffusion of Na(+) and Cl(-) in water but similar to the diffusion coefficient for protons and OH(-) ions in microcrystalline cellulose.     

Diffusive transport properties of some local anesthetics applicable for iontophoretic formulation of the drugs

As part of a general study to improve the iontophoretic delivery of local anaesthetics of the amide type, the diffusion properties of the hydrochloride salts of bupivacaine, etidocaine, lidocaine, mepivacaine, prilocaine and ropivacaine, were studied in a 1% w/w agarose hydrogel. A source drug solution (25 mM) was placed in contact with the gel and, after an appropriate time, the drug concentration profile in the gel was analyzed to give a diffusion coefficient, D. The values of Dx10(10) expressed in m(2) s(-1) were: (bupi) 6.71, (eti) 6.71, (ropi) 6.39, (mepi) 7.31, (lido) 7.49 and (prilo) 7.76. For comparative reasons, the diffusion coefficient for LidHCl in an aqueous solution according to the Nernst-Hartley relation for the diffusion of ion-pairs was calculated, hereby taking into account ionic activity of LidH+ and Cl-. The diffusion coefficient thus obtained was 7.76x10(-10) m2 s-1 at infinite dilution. The relationship between the molecular weight of the compounds and the diffusion coefficient was investigated.     

Characterization of the effects of drug addition on the structure of glyceryl monoolein/water gel systems using low frequency dielectric spectroscopy.

The influence of propantheline bromide incorporation on the phase structure of glyceryl monoolein/water systems has been investigated using low-frequency dielectric spectroscopy over a frequency range of 10(-2) to 10(6) Hz at 20 degrees C. The responses of glyceryl monoolein systems composed of 10% and 30% w/w were measured and the spectra modeled using an equivalent circuit based on the Maxwell-Wagner theory.1,2 Marked changes in the dielectric responses of the systems were noted on addition of the propantheline bromide at concentrations up to 10% w/w. For the lamellar (10% w/w water) glyceryl monoolein systems, an increase in the imaginary permitivity was seen, corresponding to an increase in conductivity due to the presence of additional ionic species within the system. Evidence was also obtained for the incorporation of the drug directly into the lipid bilayers, particularly at higher concentrations (10% drug) at which dielectric behavior corresponding to bilayer disruption was seen. Incorporation of 3% and 5% w/w drug into the cubic phase systems (30% w/w water) resulted in a change to the lamellar phase. However, circuit modeling indicated that the system formed structures which showed features of both the lamellar and cubic phases at 3% w/w drug loadings. The study has therefore demonstrated that dielectric analysis may provide a novel means of studying the effects of drug incorporation on the phase behavior of complex gel systems.     

Influence of hydration on epidermal tissue

The influence of hydration on the dynamic properties of rat epidermal skin has been determined with the use of solid-state NMR. Samples were prepared with varying degrees of hydration using deuterium oxide and then subjected to CP-MAS (cross-polarization-magic-angle spinning) with a variable contact time. By fitting the carbon magnetization as a function of contact time, estimates of the rates of polarization transfer and decay of magnetization were obtained. Increasing water content up to 50% (w/w) caused a progressive decrease in the apparent rate of proton-carbon transfer of polarization as well as an accelerated decay of the carbonyl magnetization. This may indicate that there is greater mobility of the skin components in the presence of water. The results are suggestive for providing quantitative information for the change in the effective diffusion coefficient of water in skin with increasing hydration.     

Saturable metabolism and the acute toxicity of 1,1-dichloroethylene.

The toxic effects of single, oral doses of 1,1-dichloroethylene (1,1-DCE) are caused by its metabolites. When saturable, enzymatic production of a toxic intermediate regulates toxicity, the observed inhalation toxicity, at sufficiently high concentrations, will depend on the duration of exposure and be relatively independent of the ambient concentration. The inhalation toxicity of 1,1-DCE was examined in fasted male rats to ascertain its dependence on both 1,1-DCE concentration and the duration of exposure. Immature rats (100–150 g) were exposed to 200 ppm 1,1-DCE for durations up to 2 hr. Pentobarbital sleep times (PBST) were significantly increased after exposures as brief as 0.5 hr. Intubation of immature rats with 1,1-DCE produced extensive dilation and vacuolization of the endoplasmic reticulum (ER). While young rats were more susceptible to 1,1-DCE than older rats (> 200 g), extensive damage to the ER (the presumed site of 1,1-DCE metabolism) during exposure precluded their use in determining the inhalation dose-effect curves. With older rats, PBST were not increased during exposure. The concentration-mortality curve for 4-hr exposures increased sharply between 100 and 200 ppm, but was virtually flat (i.e., concentration independent) between 200 and 1000 ppm. The LT50 (the time of exposure required to kill half an exposed group at a given concentration) only varied between 4.1 and 2.4 hr as concentration increased from 200 to 1000 ppm. Failure of 1,1-DCE to adhere to a concentration × time relationship is further evidence of a role of saturable, enzymatic activation in the expression of its toxicity.     

Combined surface pressure-interfacial shear rheology studies of the interaction of proteins with spread phospholipid monolayers at the air-water interface

The adsorption of two model proteins, catalase and lysozyme, to phospholipid monolayers spread at the air–water interface has been studied using a combined surface pressure-interfacial shear rheology technique. Monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DPPG) and DPPC:DPPG (7:3) were spread on a phosphate buffer air–water interface at pH 7.4. Protein solutions were introduced to the subphase and the resultant changes in surface pressure and interfacial storage and loss moduli were recorded with time. The results show that catalase readily adsorbs to all the phospholipid monolayers investigated, inducing a transition from liquid-like to gel-like rheological behaviour in the process. The changes in surface rheology as a result of the adsorption of catalase increase in the order DPPC < DPPC:DPPG < DPPG. Lysozyme behaves in a similar manner beneath a DPPG monolayer, but shows no measurable differences when injected beneath DPPC or the DPPC:DPPG (7:3) mixed monolayer. It is proposed that DPPG monolayers are more susceptible to penetration by adsorbing protein molecules. The interaction between DPPG and lysozyme is further enhanced due to electrostatic interactions between the negatively charged DPPG and the positively charged lysozyme.     

Controlled drug release from gels using surfactant aggregates: I. Effect of lipophilic interactions for a series of uncharged substances.

Gels are often used for the delivery of drugs because they have rheological properties that will give a long residence time. Most pharmaceutical gels consist of approximately 99% water and a polymer matrix that will not hinder the release of drugs with a small molecular weight. To fully take advantage of the residence time, it is necessary to have a sustained drug release. In this paper it is suggested that surfactant micelles can be used to control the release from gels. The in vitro release under physiological conditions of five parabens from four different poly(acrylic acid) gels (Carbopol 934, 940, 1342) and one gellan gum (Gelrite) gel was measured using a USP dissolution bath modified for gels, and the diffusion coefficients were calculated. The diffusion coefficient of uncharged parabens was generally lower in gels with lipophilic modifications, such as C1342, and the greatest effect was seen for butylparaben, with a diffusion that was 25% lower than that in C934 (lacking lipophilic modification). Addition of surfactant micelles to gels delayed the release of all the uncharged drugs in all types of gels studied. The slowest release was seen for butylparaben in a lipophilically modified gel with micelles present. The diffusion coefficient in such a system was almost 30 times smaller than that in C934 without micelles.     

Improvement of clonazepam release from a Carbopol hydrogel.

The performance of Tween 80, Tween 60, oleic acid, oleyl alcohol and Azone as enhancers of clonazepam permeation from a Carbopol hydrogel through a cellulose nitrate membrane was investigated. The effect of incorporating methyl beta-cyclodextrin (DS 1.8) in combination with clonazepam as a solid phase into some vehicles was also tested. In vitro release studies were carried out with a Sartorius apparatus and the following parameters were evaluated: drug solubility in the vehicle; partition coefficient of the drug between lauryl alcohol (the solvent which impregnates the membrane) and the vehicle; steady state flux; permeability constant; diffusion coefficient; lag time. The release kinetics followed a nearly zero-order pattern, although the diffusion-controlled mechanism might also have been operative. Maximum drug release (2.5 times that of the gel base) was achieved for the formulation containing clonazepam and methyl beta-cyclodextrin in a 1:1 (mol/mol) ratio as a solid phase, in a vehicle composed of water, propylene glycol, Tween 80 and Azone at a mass fraction of 43%, 50%, 2% and 5%, respectively.     

Alteration in mitochondrial function and glutamate metabolism affected by 2-chloroethanol in primary cultured astrocytes

The aim of this study was to explore the mechanisms that contribute to 1,2-dichloroethane (1,2-DCE) induced brain edema by focusing on alteration of mitochondrial function and glutamate metabolism in primary cultured astrocytes induced by 2-chloroethanol (2-CE), a metabolite of 1,2-DCE in vivo. The cells were exposed to different levels of 2-CE in the media for 24 h. Mitochondrial function was evaluated by its membrane potential and intracellular contents of ATP, lactic acid and reactive oxygen species (ROS). Glutamate metabolism was indicated by expression of glutamine synthase (GS), glutamate–aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) at both protein and gene levels. Compared to the control group, exposure to 2-CE could cause a dose dependent damage in astrocytes, indicated by decreased cell viability and morphological changes, and supported by decreased levels of nonprotein sulfhydryl (NPSH) and inhibited activities of Na⁺/K⁺-ATPase and Ca^2 +-ATPase in the cells. The present study also revealed both mitochondrial function and glutamate metabolism in astrocytes were significantly disturbed by 2-CE. Of which, mitochondrial function was much vulnerable to the effects of 2-CE. In conclusion, our findings suggested that mitochondrial dysfunction and glutamate metabolism disorder could contribute to 2-CE-induced cytotoxicity in astrocytes, which might be related to 1,2-DCE-induced brain edema.