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PubMed2006

Removal of chloroform from biodegradable therapeutic microspheres by radiolysis.

Radioactive holmium-166 loaded poly(l-lactic acid) microspheres are promising systems for the treatment of liver malignancies. These microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method using chloroform. After preparation the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. It was observed that relatively large amounts of residual chloroform (1000-6000 ppm) remained in the microspheres before neutron irradiation. Since it is known that chloroform is susceptible for high-energy radiation, we investigated whether neutron and gamma irradiation could result in the removal of residual chloroform in HoAcAc-loaded and placebo PLLA-MS by radiolysis. To investigate this, microspheres with relatively high and low amounts of residual chloroform were subjected to irradiation. The effect of irradiation on the residual chloroform levels as well as other microsphere characteristics (morphology, size, crystallinity, molecular weight of PLLA and degradation products) were evaluated. No chloroform in the microspheres could be detected after neutron irradiation. This was also seen for gamma irradiation at a dose of 200 kGy phosgene, which can be formed as the result of radiolysis of chloroform, was not detected with gas chromatography-mass spectrometry (GC-MS). A precipitation titration showed that radiolysis of chloroform resulted in the formation of chloride. Gel permeation chromatography and differential scanning calorimetry showed a decrease in molecular weight of PLLA and crystallinity, respectively. However, no differences were observed between irradiated microsphere samples with high and low initial amounts of chloroform. In conclusion, this study demonstrates that neutron and gamma irradiation results in the removal of residual chloroform in PLLA-microspheres.

Biodegradation, Environmental↗
PubMed2001

Effect of chloroform on dichloroacetic acid and trichloroacetic acid-induced hypomethylation and expression of the c-myc gene and on their promotion of liver and kidney tumors in mice.

Chloroform, dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are mouse liver carcinogens that are chlorine disinfection by-products found in drinking water. The effect of chloroform on DCA and TCA-induced hypomethylation and expression of the c-myc gene and on their promotion of liver and kidney tumors was determined. B6C3F1 mice were administered 0, 400, 800 and 1600 mg/l chloroform in drinking water and 500 mg/kg DCA or TCA-administered daily by gavage. DCA, TCA and to a lesser extent chloroform decreased the methylation and increased the mRNA expression of the c-myc gene. Co-administering chloroform prevented only DCA and not TCA-induced hypomethylation and increased mRNA expression of the gene. The effect of chloroform on tumor promotion by DCA and TCA was determined in female and male B6C3F1 mice initiated on day 15 of age with N-methyl-N-nitrosourea. Starting at 5 weeks of age, the mice received in their drinking water DCA (3.2 g/l) or TCA (4.0 g/l) with 0, 800 or 1600 mg/l chloroform until they were killed at 36 weeks. Liver tumors promoted by DCA and TCA were predominantly basophilic except for DCA-treated female mice that were eosinophilic. Only DCA promoted foci of altered hepatocytes and they were eosinophilic in both sexes. Chloroform prevented DCA, but not TCA promotion of liver foci and tumors. In male mice, TCA promoted kidney tumors while DCA promoted kidney tumors only when co-administered with chloroform. Hence, chloroform prevented the hypomethylation and increased mRNA expression of the c-myc gene and the promotion of liver tumors by DCA, while enhancing DCA-promotion of kidney tumors. Thus, the concurrent exposure to two carcinogens, chloroform and DCA resulted in less than additive activity in one organ and synergism in another organ.

Animals↗
PubMed2001

Chronic toxicity of chloroform to Japanese medaka fish.

Japanese medaka (Oryzias latipes) were continually exposed in a flow-through diluter system for 9 months to measured chloroform concentrations of 0.017, 0.151, or 1.463 mg/L. Parameters evaluated were hepatocarcinogenicity, hepatocellular proliferation, hematology, and intrahepatic chloroform concentration. Histopathology was evaluated at 6 and 9 months. Chloroform was not hepatocarcinogenic to the medaka at the concentrations tested. Chronic toxicity was evidenced at these time points by statistically significant ([alpha] = 0.05) levels of gallbladder lesions and bile duct abnormalities in medaka treated with 1.463 mg/L chloroform. We assessed hepatocellular proliferation by exposing test fish to 5-bromo-2'-deoxyuridine in the aquarium water for 72 hr after 4 and 20 days of chloroform exposure; we then quantified area-labeling indices of the livers using computer-assisted image analysis. We observed no treatment-related increases in cellular proliferation. We analyzed cells in circulating blood in medaka after 6 months of chloroform exposure. Hematocrit, leukocrit, cell viability, and cell counts of treated fish were not significantly different from those of control fish. Using gas chromatography (GC), we evaluated intrahepatic concentrations of chloroform in fish after 9 months of exposure. Livers from the 0.151 and 1.463 mg/L chloroform-treated fish had detectable amounts of chloroform, but these levels were always lower than the aquaria concentrations of chloroform. Thus, it appeared that chloroform did not bioaccumulate in the liver. Unidentified presumptive metabolite peaks were found in the GC tracings of these fish livers.

Animals↗
PubMed1982

Chloroform induction of ornithine decarboxylase activity in rats.

Chloroform is a drinking water contaminant that has been demonstrated to be carcinogenic to mice and rats resulting in an increased incidence of liver and kidney tumors, respectively. The mechanism of chloroform carcinogenicity might be by tumor initiation and/or promotion. Since induction of ornithine decarboxylase (ODC) activity has been proposed as a molecular marker for tumor promoters, we have investigated the effect of chloroform on ODC activity in rats. Chloroform induced a dose-dependent increase of hepatic ODC with an apparent threshold at 100 mg/kg body weight. Female rats were two to four times more susceptible to to chloroform. Upon daily dosing of chloroform for 7 days the liver became less susceptible, with the last dose of chloroform resulting in only 10% of the activity observed after a single dose. Nuclear RNA polymerase I activity was also induced by chloroform. Chloroform, rather than increasing the activity of renal ODC, resulted in a 35% reduction. The induction by chloroform of hepatic ODC activity might be associated with regenerative hyperplasia while the renal carcinogenicity of chloroform could not be demonstrated to be associated with ODC induction.

Animals↗
PubMed2002

Role of ryanodine receptors in chloroform-induced contraction in Swine tracheal smooth muscle.

Chloroform has been reported to induce inhalation intoxication in the respiratory tract. The purpose of this study was to investigate the effects and mechanisms of chloroform on muscle contraction in isolated swine tracheal smooth muscle. Chloroform (30-1000 ppm) reversibly and concentration-dependently provoked smooth muscle contraction. Muscarinic and alpha-adrenergic receptor antagonists did not alter chloroform-induced muscle contraction, indicating muscarinic and alpha-adrenergic stimulation may not be involved in chloroform-induced responses. Caffeine (10 mM) was observed to directly evoke tracheal smooth muscle contraction, but ryanodine (1 microM) was not. However, ryanodine and caffeine abolished chloroform-induced smooth muscle contraction by 80.0 +/- 8.0 and 79.6 +/- 6.0%, respectively. Caffeine combined with ryanodine completely blocked chloroform-induced contractile responses. Thus, it suggests that chloroform released Ca(2+) from ryanodine-sensitive internal Ca(2+) pools. Although short-term removal of Ca(2+) from extracellular environment slightly decreased chloroform-induced contractile responses, L-type Ca(2+) channel blockers did not alter tracheal smooth muscle contraction induced by chloroform. Collectively, our results indicated that chloroform directly and concentration-dependently provoked muscle contraction in swine tracheal smooth muscle, which may result from the activation of ryanodine receptor Ca(2+) release channel in sarcoplasmic reticulum but may not depend on muscarinic and adrenergic activation and Ca(2+) entry from the extracellular environment.

Adrenergic Agents↗
PubMed1994

Route of administration determines whether chloroform enhances or inhibits cell proliferation in the liver of B6C3F1 mice.

Chloroform administered by gavage has been shown to induce liver cancer in B6C3F1 mice; however, when administered in the drinking water, chloroform inhibited liver cancer in mice. The effect of chloroform administered by these two routes upon cell proliferation in mouse liver was determined. Female B6C3F1 mice were divided into five treatment groups: (1) chloroform (263 mg/kg body wt) by gavage in corn oil, (2) 1,800 ppm chloroform in drinking water, (3) 1,800 ppm chloroform in drinking water plus 10 ml/kg body wt corn oil by gavage, (4) 10 ml/kg body wt corn oil by gavage, and (5) untreated controls. Five days prior to termination, the mice were implanted subcutaneously with a 7-day osmotic minipump containing 30 mg/ml bromodeoxyuridine. Mice were terminated after 5, 12, 33, and 159 days of exposure. Chloroform administered by gavage in corn oil increased cell proliferation at all terminations, while, when administered in drinking water, cell proliferation was inhibited on Days 5 and 12. At 33 and 159 days, chloroform administered in the drinking water did not affect cell proliferation, even though the dose received by the animals was comparable to that given in corn oil by gavage. Therefore, cell proliferation was enhanced only by chloroform administered in corn oil by gavage, which corresponds to the hepatocarcinogenicity of chloroform administered by this route.

Administration, Oral↗
PubMed1985

The effect of moisture on the adsorption of chloroform by activated carbon.

The effect of moisture on the ability of a granular activated carbon to adsorb chloroform vapor from a flowing airstream was studied under three test conditions: (1) chloroform and water vapor were introduced concurrently into a dry carbon bed; (2) dry chloroform was introduced into a humidified carbon bed; (3) humidified chloroform was introduced into a carbon bed at the same relative humidity. The criterion for bed performance was the time when the downstream chloroform concentration was 1% of that in the inlet stream. Chloroform concentration was essentially constant at 108 +/- 2 micrograms/cm3; relative humidities (RH) varied from 0 to 97%. No RH effect on the adsorption of chloroform by the carbon was observed in test (1); tests (2) and (3) showed monotonic decreases in chloroform adsorption for RH greater than 40%. These results indicated that, for a dry carbon bed, the 1% breakthrough time for chloroform adsorbed from atmospheres of RH from 13% to 95% was essentially the same as that when RH = 0%. For humidified carbon beds, no change in 1% breakthrough time for chloroform was observed until RH was greater than 40%.

Adsorption↗
PubMed2000

Ca(2+) mobilization evoked by chloroform in Madin-Darby canine kidney cells.

The effect of chloroform on Ca(2+) mobilization in Madin-Darby canine kidney cells was examined by using Fura-2 as a Ca(2+) probe. Chloroform (24-248 mM) concentration dependently increased intracellular Ca(2+) concentration ([Ca(2+)](i)). Ca(2+) removal inhibited the Ca(2+) signals evoked by 93 to 248 mM chloroform by reducing both the initial rise and the sustained phase. In Ca(2+)-free medium, pretreatment with 93 mM chloroform abolished the Ca(2+) release induced by 1 microM thapsigargin, an endoplasmic reticulum Ca(2+) pump inhibitor, and partially reduced the Ca(2+) release induced by 2 microM carbonylcyanide m-chlorophenylhydrazone, a mitochondrial uncoupler. Pretreatment with carbonylcyanide m-chlorophenylhydrazone and thapsigargin to deplete the Ca(2+) stores in mitochondria and the endoplasmic reticulum, respectively, only partially inhibited chloroform-induced Ca(2+) release. This suggests that chloroform released Ca(2+) from multiple internal pools. The addition of 3 mM Ca(2+) increased [Ca(2+)](i) after pretreatment with 93 mM chloroform in Ca(2+)-free medium. La(3+) (1 mM) partially inhibited the [Ca(2+)](i) increase induced by 93 mM chloroform. Chloroform (93 mM)-induced Ca(2+) release was not altered when the formation of inositol-1,4,5-trisphosphate was abolished by U73122 (2 microM), a phospholipase C inhibitor, but was inhibited by 90% by inhibition of phospholipase A(2) with 40 microM aristolochic acid. Collectively, we found that 93 mM chloroform increased [Ca(2+)](i) in Madin-Darby canine kidney cells by releasing Ca(2+) from multiple stores in a manner independent of the formation of inositol-1,4,5-trisphosphate, followed by Ca(2+) entry from external medium. Other solvents, such as ethanol, methanol, and DMSO, did not affect the resting [Ca(2+)](i) at a concentration of 248 mM.

Adenosine Triphosphate↗
PubMedDate not supplied

Infectious bursal disease viral RNA amplification using RT/PCR from bursa tissue following phenol: chloroform inactivation of the virus.

The preservation of viable infectious agents for future studies could create complicated logistic problems, and at times it is not feasible. Methods for preserving the genetic integrity of inactivated agents would not only facilitate these studies but would also make it possible to transport inactivated preparations around the world. In this report, the effect of inactivation on the genetic material of infectious bursal disease virus (IBDV) was studied. Tissues from the bursa of Fabricius of birds experimentally infected 3 days earlier with the classic STC strain of IBDV were collected and immediately placed in a solution of phenol:chloroform:isoamyl alcohol (25:24:1) for 24, 48, 72, or 96 hr. Infected bursal tissue not treated with the phenol:chloroform solution and uninfected phenol: chloroform bursal tissue were used as controls. In a separate experiment, bursal tissues collected 5 days following infection of specific-pathogen-free birds with the classic STC or variant 1084-E strain were placed in the phenol:chloroform solution for 2 wk. All bursal samples were tested for viable IBDV following phenol:chloroform treatment. The tissues were washed in phosphate-buffered saline to remove phenol and then homogenized. Viability of the viruses in homogenized bursal tissue was examined by inoculation of embryonated chicken eggs. Viable IBDV was not observed in any phenol:chloroform-treated bursal tissue but was observed in the infected but non-phenol:chloroform-treated control bursa. The reverse transcriptase/polymerase chain reaction (RT/PCR) was used to test the integrity of the viral RNA. Viral RNA from the nontreated control and all infected bursal samples treated with phenol:chloroform solution at all the time points examined were transcribed into DNA, and a 394-bp fragment of the VP2 gene was amplified using specific primers in the PCR. The RT/PCR assay was negative using the phenol:chloroform-treated uninfected bursal tissue. This study clearly demonstrated that phenol:chloroform treatment of infected bursal tissue inactivated the classic and variant IBDV strains tested and preserved the viral RNA for use in the RT/PCR assay.

Animals↗
PubMed2005

Molecular modeling of phase behavior and microstructure of acetone-chloroform-methanol binary mixtures.

Force fields based on a Lennard-Jones (LJ) 12-6 plus point charge functional form are developed for acetone and chloroform specifically to reproduce the minimum pressure azeotropy found experimentally in this system. Point charges are determined from a CHELPG population analysis performed on an acetone-chloroform dimer. The required electrostatic surface for this dimer is determined from ab initio calculations performed with MP2 theory and the 6-31g++(3df,3pd) basis set. LJ parameters are then optimized such that the liquid-vapor coexistence curve, critical parameters, and vapor pressures are well reproduced by simulation. Histogram-reweighting Monte Carlo simulations in the grand canonical ensemble are used to determine the phase diagrams for the binary mixtures acetone-chloroform, acetone-methanol, and chloroform-methanol. The force fields developed in this work reproduce the minimum pressure azeotrope in the acetone-chloroform mixture found in experiment. The predicted azeotropic composition of x(CHCl3) = 0.77 is in fair agreement with the experimental value of x(CHCl3)expt = 0.64. The new force fields were also found to provide improved predictions of the pressure-composition behavior of acetone-methanol and chloroform-methanol when compared to other force fields commonly used for vapor-liquid equilibria calculations. NPT simulations were conducted at 300 K and 1 bar for equimolar mixtures of acetone-chloroform, acetone-methanol, and methanol-chloroform. Analysis of the microstructure reveals significant hydrogen bonding occurring between acetone and chloroform. Limited interspecies hydrogen bonding was found in the acetone-methanol or chloroform-methanol mixtures.

Journal Article↗
PubMed1997

Differential display identified changes in mRNA levels in regenerating livers from chloroform-treated mice.

The nongenotoxic-cytotoxic carcinogen chloroform induces liver necrosis, regenerative cell proliferation, and, eventually, liver tumors in female B6C3F1 mice when administered by gavage at doses of 238 or 477 mg/kg/d. Administration of 1800 ppm of chloroform in the drinking water results in similar daily doses but does not produce liver toxicity or cancer. The differential-display technique was used to compare the expression of a subset of mRNAs in normal (control) and regenerating liver after chloroform-induced toxicity to define the proportion of genes whose expression changes under hepatotoxic conditions and to identify the genes that might play a role in regeneration and perhaps cancer. RNA was purified from the livers of female B6C3F1 mice after 4 d or 3 wk of gavage treatment with 3, 238, or 477 mg/kg/d of chloroform or treatment with 1800 ppm chloroform in drinking water. There was a remarkably high degree of consistency of gene expression among the animals and across dose and treatment groups as visualized by the differential-display technique. Of the 387 bands observed, only four (about 1%) changed expression in regenerating liver. The genes were assigned locus names by GenBank after sequence submission. The genes with increased mRNA levels as confirmed by northern blot analysis were MUSTIS21, a mouse primary response gene induced by growth factors and tumor promoters; MUSMRNAH, a gene highly homologous to a human gene isolated from a prostate carcinoma cell line; and MUSFRA, a novel gene. The novel gene MUSFRB exhibited decreased mRNA levels. No change in expression was seen among control mice given the nontoxic regimens of 3 mg/kg/d chloroform or 1800 ppm chloroform in drinking water, indicating that changes in expression were associated with toxicity and regeneration rather than chloroform per se. These genes and others that may be identified by expanding this approach may play a role in regeneration and perhaps in the process of chloroform-induced carcinogenesis in rodent liver.

Animals↗
PubMed1995

Different contributions of cytochrome P450 2E1 and P450 2B1/2 to chloroform hepatotoxicity in rat.

The contribution of cytochrome P450 isozymes CYP2E1 and CYP2B1/2 to chloroform-induced hepatotoxicity taken at 18 hr after the treatment was investigated in rats treated with n-hexane as an inducer of CYP2E1, 2-hexanone as an inducer of CYP2E1 and CYP2B1/2, and phenobarbital (PB) as an inducer of CYP2B1/2. Hepatic damage was evaluated by gross measurement of plasma alanine aminotransferase activity and histopathological examination. All treatments potentiated chloroform-induced hepatic damage. In n-hexane-pretreated rats, the damage was maximal with the middle dose of chloroform (0.2 ml/kg), whereas the damage increased with dose in rats treated with 2-hexanone or PB. The degree of hepatic damage induced with the three pretreatments was in the following order: n-hexane > 2-hexanone = PB with the middle dose of chloroform and PB >> 2-hexanone > n-hexane with the high dose (0.5 ml/kg); little difference among the pretreatments was seen with the low dose (0.1 ml/kg). These findings suggest that CYP2E1 is a low Km isoform and CYP2B1/2 a high Km isoform for chloroform activation. CYP2E1-dependent hepatic damage was characterized by ballooned hepatocytes, which were restricted to the centrilobular area; with CYP2B1/2, more necrotic than ballooned hepatocytes were seen and the necrotic hepatocytes were found not only in the centrilobular but also in the midzonal and periportal areas. Chloroform treatment did not affect the activity of N-nitrosodimethylamine N-demethylase in pretreated rats; the high dose increased the activity in control rats. In contrast, the high dose of chloroform decreased the activity of 7-pentoxyresorufin O-depentylase in all induced rats but not in controls. Immunoinhibition and immunoblot analyses showed that the high dose of chloroform induced CYP2E1 in control rats but decreased CYP2B1/2 in all pretreated rats. These results suggest that although both CYP2E1 and CYP2B1/2 contribute to chloroform-induced hepatic damage, they do so quite differently.

Alanine Transaminase↗
PubMed1979

Biotransformation of chloroform by rat and human liver microsomes; in vitro effect on some enzyme activities and mechanism of irreversible binding to macromolecules.

The effects of chloroform on some rat microsomal enzyme activities were studied in vitro. Maximum inhibition of oxygen consumption, NADPH oxidase and NADPH-cytochrome c reductase was observed at 0.5 mM chloroform; prior metabolization of CHCl3 by microsomal monooxygenases increased inhibition by about 50% at 0.2-0.5 mM chloroform. Higher concentrations produced a paradoxical reversal of inhibition, whereas p-nitroanisole demethylase was steadily inhibited by about 50% up to 10 mM chloroform. Irreversible binding of 14CHCl3 was confirmed to depend on chloroform metabolization by monooxygenases. The increased irreversible binding due to phenobarbital induction is accompanied by a diminished affinity towards chloroform as shown by increased KM of irreversible binding, and a higher spectral dissociation constant KS. Aminoacids with nucleophilic functions (histidine, cysteine) partially prevented the irreversible binding of chloroform metabolites to microsomes; non-volatile radioactive derivatives were recovered in trichloracetic acid supernatants when microsomes were incubated with cysteine, but not with histidine. Phosgene has been demonstrated as a biological metabolite of chloroform: its possible reactions with nucleophilic groups of macromolecules, water and added aminoacids partly explain these experimental data. Similar results were obtained with human microsomes, showing that chloroform hepatotoxicity in man could involve the same mechanisms.

Animals↗
PubMed1990

Multiple activation of chloroform in hepatic microsomes from uninduced B6C3F1 mice.

The covalent binding of 14C-label to proteins and lipids was measured after incubation of hepatic microsomes from B6C3F1 mice with different concentrations of [14C]chloroform and oxygen. The effect of reduced glutathione on the covalent binding curves was also investigated. The results indicated that chloroform is activated through three processes: the first, oxidative, shows high affinity for chloroform and low affinity for oxygen; the second, also requiring oxygen, shows low affinity for chloroform and high affinity for oxygen; and the third, showing low affinity for chloroform, is inhibited by oxygen. The covalent binding associated with the oxidative processes is very effectively prevented by GSH. The reactive metabolites formed by the O2-inhibited mechanism are not efficiently scavenged by GSH and presumably are radicals that are produced reductively. The major conclusions which can be drawn from these results are: (i) The anoxic bioactivation of chloroform can cause high levels of covalent binding. This is at variance with the current opinion that the chloroform anoxic bioactivation occurs to a negligible extent. (ii) The damages produced under the usual in vitro experimental conditions by the oxidative biotransformation of chloroform, may be strongly limited by the physiological conditions of the liver. The features of the three processes described may help in understanding the mechanism of toxicity of chloroform.

Animals↗
PubMed2006

Adaptive tolerance in mice upon subchronic exposure to chloroform: Increased exhalation and target tissue regeneration.

The aims of the present study were to characterize the subchronic toxicity of chloroform by measuring tissue injury, repair, and distribution of chloroform and to assess the reasons for the development of tolerance to subchronic chloroform toxicity. Male Swiss Webster (SW) mice were given three dose levels of chloroform (150, 225, and 300 mg/kg/day) by gavage in aqueous vehicle for 30 days. Liver and kidney injury were measured by plasma ALT and BUN, respectively, and by histopathology. Tissue regeneration was assessed by (3)H-thymidine incorporation into hepato- and nephro-nuclear DNA and by proliferating cell nuclear antigen staining. In addition, GSH and CYP2E1 in liver and kidney were assessed at selected time points. The levels of chloroform were measured in blood, liver, and kidney during the dosing regimen (1, 7, 14, and 30 days). Kidney injury was evident after 1 day with all three doses and sustained until 7 days followed by complete recovery. Mild to moderate liver injury was observed from 1 to 14 days with all three dose levels followed by gradual decrease. Significantly higher regenerative response was evident in liver and kidney at 7 days, but the response was robust in kidney, preventing progression of injury beyond first week of exposure. While the kidney regeneration reached basal levels by 21 days, moderate liver regeneration with two higher doses sustained through the end of the dosing regimen and 3 days after that. Following repeated exposure for 7, 14, and 30 days, the blood and tissue levels of chloroform were substantially lower with all three dose levels compared to the levels observed with single exposure. Increased exhalation of (14)C-chloroform after repeated exposures explains the decreased chloroform levels in circulation and tissues. These results suggest that toxicokinetics and toxicodynamics (tissue regeneration) contribute to the tolerance observed in SW mice to subchronic chloroform toxicity. Neither bioactivation nor detoxification appears to play a decisive role in the development of this tolerance.

Animals↗
PubMed2006

In vitro modulation of HERG channels by organochlorine solvent trichlormethane as potential explanation for proarrhythmic effects of chloroform.

Acute chloroform intoxication can cause depression of the central nervous system and may lead to death from lethal arrhythmias or respiratory arrest. Thus, the organic solvent is no longer in clinical use as an anaesthetic, but still plays a role in cases of suicide, homicide or inhalation for psychotropic effects. Several cases of lethal arrhythmia after intoxication with chloroform have been described. Pharmacological inhibition of cardiac "human ether-à-go-go-related gene" (HERG) potassium channels is linked to proarrhythmic effects of cardiac and noncardiac drugs. To further investigate the electrophysiological basis of the arrhythmogenic potential of chloroform, we analysed inhibitory effects of chloroform on cloned HERG potassium channels, heterologously expressed in Xenopus oocytes and in Human Embryonic Kidney (HEK 293) cells using the double-electrode voltage-clamp technique and the whole-cell patch-clamp technique, respectively. In HEK cells, chloroform blocked HERG tail currents with an IC(50) of 4.97mM. Biophysical properties were further investigated in the Xenopus oocyte expression system. Onset and wash-out of block was fast and inhibition was completely reversible. Chloroform did not alter channel activation, however, direct channel inactivation was accelerated significantly. Steady-state-inactivation of HERG was not affected. Chloroform dependent block of HERG channels was voltage dependent with a decrease of inhibition at more positive membrane potentials. No frequency-dependence of block could be observed. In summary, chloroform blocked HERG potassium channels probably in a toxicologically relevant concentration. These findings contribute to the pathophysiology of proarrhythmic effects in acute chloroform intoxication.

Animals↗
PubMed1989

Evaluation of alternatives to chloroform in endodontic practice.

Chloroform is used in endodontics for plasticizing gutta-percha points and for facilitating removal of gutta-percha root canal fillings in need of re-treatment. Adverse health effects from exposure to chloroform have been reported, and to improve occupational health, it would be advantageous if a less hazardous solvent could replace chloroform. In this study, methylene chloride, methyl chloroform, tetrahydrofuran, xylol and eucalyptol were tested for their capacity to dissolve or soften gutta-percha points compared with chloroform. The effect of the test solvents was assessed by measuring the depth of penetration of a small indentor of fixed weight and shape into a gutta-percha disk covered with the test solution for various time periods. Chloroform showed the most pronounced effect, followed by methylene chloride, tetrahydrofuran, and methyl chloroform. When both occupational health and gutta-percha solvent capacity were considered, methyl chloroform seemed to be an interesting alternative to chloroform.

Chloroform↗
PubMed2006

Protective effect of a 43 kD protein from the leaves of the herb, Cajanus indicus L on chloroform induced hepatic-disorder.

Cajanus indicus is a herb with medicinal properties and is traditionally used to treat various forms of liver disorders. Present study aimed to evaluate the effect of a 43 kD protein isolated from the leaves of this herb against chloroform induced hepatotoxicity. Male albino mice were intraperitoneally treated with 2 mg/kg body weight of the protein for 5 days followed by oral application of chloroform (0.75 ml/kg body weight) for 2 days. Different biochemical parameters related to physiology and pathophysiology of liver, such as, serum glutamate pyruvate transaminase and alkaline phosphatase were determined in the murine sera under various experimental conditions. Direct antioxidant role of the protein was also determined from its reaction with Diphenyl picryl hydroxyl radical, superoxide radical and hydrogen peroxide. To find out the mode of action of this protein against chloroform induced liver damage, levels of antioxidant enzymes catalase, superoxide dismutase and glutathione-S-transferase were measured from liver homogenates. Peroxidation of membrane lipids both in vivo and in vitro were also measured as malonaldialdehyde. Finally, histopathological analyses were done from liver sections of control, toxin treated and protein pre- and post-treated (along with the toxin) mice. Levels of serum glutamate pyruvate transaminase and alkaline phosphatase, which showed an elevation in chloroform induced hepatic damage, were brought down near to the normal levels with the protein pretreatment. On the contrary, the levels of antioxidant enzymes such as catalase, superoxide dismutase and glutathione-S-transferase that had gone down in mice orally fed with chloroform were significantly elevated in protein pretreated ones. Besides, chloroform induced lipid peroxidation was effectively reduced by protein treatment both in vivo and in vitro. In cell free system the protein effectively quenched diphenyl picryl hydroxyl radical and superoxide radical, though it could not catalyse the breakdown of hydrogen peroxide. Post treatment with the protein for 3 days after 2 days of chloroform administration showed similar results. Histopathological studies indicated that chloroform induced extensive tissue damage was less severe in the mice livers treated with the 43 kD protein prior and post to the toxin administration. Results from all these data suggest that the protein possesses both preventive and curative role against chloroform induced hepatotoxicity and probably acts by an anti-oxidative defense mechanism.

Alanine Transaminase↗