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At least 19 recordsLinked to original sources
PubMed1986

NADPH-dependent and -independent loss of cytochrome P-450 in control and phenobarbital-induced rat hepatic microsomes incubated with carbon tetrachloride.

Carbon tetrachloride-mediated loss of cytochrome P-450 has been compared in hepatic microsomes from untreated and phenobarbital-treated rats. At concentrations of carbon tetrachloride greater than 2.5 mM, a direct effect (i.e., NADPH- independent) on cytochrome P-450 was observed. This apparently arose from the "solvent" properties of carbon tetrachloride as this effect could be duplicated with the physically similar alkyl halide 1,2-dibromo-3-chloropropane. NADPH-dependent loss of cytochrome P-450 occurred at lower concentrations with maximal response occurring at 2.5-5.0 mM. Residual cytochrome P-450 at these concentrations was similar in untreated and phenobarbital-treated microsomes. Mixed-function oxidase activities in phenobarbital-treated microsomes were reduced to levels below those of uninduced controls. The 52-kDa polypeptide(s) in untreated microsomes and that specifically induced in phenobarbital-treated microsomes were susceptible to NADPH-dependent carbon tetrachloride incubation. These data suggest that the susceptibility of specific forms of cytochrome P-450 to carbon tetrachloride can be duplicated in in vitro incubation. Furthermore, data on the direct action of carbon tetrachloride suggest that this route of damage must be taken into consideration when concentrations of carbon tetrachloride of 2.5 mM or greater are used in in vitro incubation systems.

Animals↗
PubMed1993

Induction of serum-borne immunomodulatory factors in B6C3F1 mice by carbon tetrachloride. I. Carbon tetrachloride-induced suppression of helper T-lymphocyte function is mediated by a serum borne factor.

Following carbon tetrachloride-induced liver injury, hepatotrophic factors are synthesized and released into the serum to facilitate the regeneration of damaged hepatic tissue. We investigated the possibility that immunosuppression could be mediated through induction of a serum factor(s) because in vivo exposure of B6C3F1 mice to carbon tetrachloride selectively inhibits T-cell-dependent immune responses. Addition of mouse serum (5% by volume) obtained from mice treated with carbon tetrachloride (250 or 500 mg/kg/day for 7 days) to naive spleen cell cultures markedly suppressed the sheep red blood cell antibody-forming cell response compared to controls (P < 0.01). Immunosuppression was observed in mice sensitized with sheep red blood cells 48 h, but not 24 or 72 h, following one dose of carbon tetrachloride (1000 mg/kg). Only serum isolated from mice 48 h following exposure to a single dose of carbon tetrachloride (1000 mg/kg) suppressed the antibody-forming cell response when added in vitro to spleen cell cultures. Biodistribution studies using [14C]-labelled carbon tetrachloride demonstrated that accumulation of the [14C]-label was primarily associated with excretory organs (liver, kidneys and lungs) but not with the serum, red blood cells, or spleen. Surprisingly, 24 and 48 h following exposure to [14C]-labelled carbon tetrachloride, an increase in radioactivity was detected in the thymus. The distinct profile of immunosuppressive activity associated with serum isolated from carbon tetrachloride-treated mice and the biodistribution studies clearly demonstrating a negligible amount of carbon tetrachloride or metabolites in the serum strongly implicate the role of a carbon tetrachloride-induced serum borne immunosuppressive factor.

Animals↗
PubMed1990

Direct observation of spin-trapped carbon dioxide radicals in hepatocytes exposed to carbon tetrachloride.

Carbon dioxide radical adducts of the spin trapping agent, alpha-phenyl N-t-butyl nitrone (PBN), have been observed to occur in the urine and bile of rats exposed to carbon tetrachloride as well as in perfusates of liver in which the perfusion medium contained carbon tetrachloride (Connor et al., J. Biol. Chem., 261, 4542, (1986]. The carbon dioxide adduct was proven to be derived from CCl4 by use of 13-C-labelled compound. These adducts were not observed in the liver itself suggesting that they might be rapidly secreted from the liver. However, using isolated hepatocytes, we have demonstrated that the carbon dioxide radical adduct can be observed directly in the liver cells as it is formed. Since this water-soluble adduct cannot be extracted by non-aqueous solvents such as chloroform or toluene, its formation in liver in vivo or in perfused livers was not detected. Lowering the oxygen tension in the system diminished the intensity of production of the carbon dioxide adduct, consistent with the adduct being produced as a result of .OOCCl3 generation. It is not clear the extent to which this adduct is formed as a result of the .CO2 radical or is produced by metabolic oxidation of the trichloromethyl radical adduct of PBN per se to the carbon dioxide radical adduct. The intensity of the signal of the carbon dioxide radical adduct suggests that adduct conversion may be the route of formation since it seems unlikely that a sufficient amount of the halocarbon could be metabolized to .COCl or .CO2 radicals to generate a signal of the magnitude involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

The apparent loss of cytochrome P-450 associated with metabolic activation of carbon tetrachloride.

Carbon monoxide inhibited the carbon tetrachloride-induced NADPH oxidation rate. The addition of methylviologen to the incubation mixture under the atmosphere of nitrogen resulted in the enhancement of the reductase activity of microsomes for carbon tetrachloride, as determined by chloroform formation. The addition of methylviologen also enhanced the carbon tetrachloride-induced loss of cytochrome P-450, while the apparent content of cytochrome b5 and the activity of NADPH-cytochrome c reductase remained unchanged. Under a strong inhibition of lipid peroxidation by addition of EDTA, carbon tetrachloride induced a clear loss of cytochrome P-450 to the extent similar to that seen in the absence of EDTA. These results indicate that cytochrome P-450 is directly degraded in association with the reductive metabolism of carbon tetrachloride by cytochrome P-450.

Animals↗
PubMed1994

Induction of serum borne immunomodulatory factors in B6C3F1 mice by carbon tetrachloride. Exposure to carbon tetrachloride produces an increase in B-cell number and function.

Carbon tetrachloride exposure in mice induces a serum associated immunosuppressive factor(s) that inhibits T-cell dependent immune responses. The objective of the present studies was to characterize the immunomodulatory activity of serum isolated from carbon tetrachloride-treated mice on T-cell independent humoral immune responses. Direct addition of serum isolated from carbon tetrachloride-treated mice (500 mg/kg/day for 7 days) to naive spleen cell cultures enhanced the antibody forming cell response to lipopolysaccharide as compared to serum from naive or vehicle-treated mice. Enhanced antibody forming cell responses were also observed when spleen cells isolated from carbon tetrachloride-treated mice were sensitized with this T-cell independent antigen 24 h, but not 48 h or 72 h, following exposure of mice to one dose of 500 or 1000 mg/kg of carbon tetrachloride. Additionally, spleen weight and spleen:body weight ratio were increased in mice sensitized in vivo with sheep red blood cells 24 h after exposure to a single dose of carbon tetrachloride (500 or 1000 mg/kg) as compared to naive antigen sensitized mice and mice sensitized 48 and 72 h after exposure to carbon tetrachloride. Fluorescence activated cell sorting analysis indicated that daily exposure to carbon tetrachloride (250 or 500 mg/kg for 7 days) increased the percentage of B-cells in the spleen without altering the number of TH-cell or TC/S cell populations. Taken together, these results suggest that exposure to carbon tetrachloride induces a serum borne factor(s) that produces a modest increase in the functional activity and number of B-cells in the spleen.

Adjuvants, Immunologic↗
PubMed1990

Reaction of glutathione with a free radical metabolite of carbon tetrachloride.

Carbon tetrachloride and bromotrichloromethane are both metabolized by cytochrome P-450 in the presence of phenyl-N-t-butyl nitrone PBN) to the PBN/trichloromethyl (PBN/.CCl3) and the PBN carbon dioxide anion (PBN/.CO2-) radical adducts in the liver. The formation of the latter but not the former species in perfused liver was reduced markedly by prior depletion of hepatic glutathione with either diethyl maleate or buthionine sulfoximine treatments. In microsomal incubations, the PBN/.CO2- radical adduct was detected only upon the addition of cytosol. In microsomal incubations containing PBN, CCl4, and GSH, but no added cytosol, a novel radical adduct with distinctive coupling constants was detected. This radical adduct's ESR spectrum exhibited 13C isotope effects when it was formed in an incubation containing 13CCl4 or Br13CCl3. The presence of GSH in the radical adduct is postulated based on the radical adduct's hydrophilicity and slow rate of rotation in solution. The detection of this new radical adduct, PBN/[GSH-.CCl3], establishes the reaction of GSH with a CCl4-derived free radical as a significant event in the metabolism of CBrCl3 and CCl4. The cytosolic conversion of PBN/[GSH-.CCl3] into PBN/.CO2- has been demonstrated and characterizes the PBN/.CO2- radical adduct as the product of metabolism of PBN/[GSH-.CCl3], a primary radical adduct. Thus, it is concluded that GSH rather than oxygen is obligatory for the formation of PBN/.CO2- from .CCl3 in intact cells.

Animals↗
PubMed1990

Influence of parathyroidectomy on liver glycogen in rats treated with carbon tetrachloride.

Carbon tetrachloride (CCl4) brings about a rise in cytosolic free calcium which may lead to glycogen mobilization. Therefore, glycogen and glucose-6-phosphatase (G-6-pase) levels in the liver of parathyroidectomized (PTX) rats following CCl4 treatment have been estimated. CCl4 depletes both glycogen and G-6-pase levels in the liver. PTX followed by CCl4 administration, however, fails to restore liver glycogen and G-6-pase levels. The results suggest that neither cytosolic Ca2+ nor phospholipase A2 mediation is needed for glycogen mobilization, however, glucocorticoid intervention might have a role in such mechanisms.

Animals↗
PubMed1998

Evaluation of urinary biomarkers for radical-induced liver damage in rats treated with carbon tetrachloride.

Carbon tetrachloride (CCl4) is a model compound for inducing free radical damage in liver. In this study 10 biomarkers in rats treated i.p. with three different single doses of CCl4 (0.25, 0.50, and 1.00 ml/kg body wt) were measured dose and time dependently and compared to evaluate these urinary products as noninvasive biomarkers for radical damage. Eight degradation products of lipid peroxides, namely, formaldehyde, acetaldehyde, acetone, propanal, butanal, pentanal, hexanal, and malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and coproporphyrin III were measured in this study. As general measures of toxicity, several clinical chemical parameters (n = 12) and histopathological damage were determined. A dose-dependent increase in both the clinical parameters and the lipid degradation products was found. Increases in lipid degradation products were statistically significant at doses of 0.5 and 1 ml/kg CCl4. An increase in these products was already found in the first 12 h after exposure. At the lowest dose, 0.25 ml/kg CCl4, acetaldehyde and propanal already showed a statistically significant increase as well. No change in the urinary levels of 8-OH-dG could be found in this study and a decrease in the urinary excretion of coproporphyrin III was found. It is concluded that 8-OH-dG and coproporphyrin III are not useful biomarkers for radical damage induced by CCl4. Lipid degradation products, however, are promising noninvasive biomarkers for in vivo radical damage, although the precise specificity of these biomarkers for damage induced by radicals needs to be further investigated.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1984

Effect of ethanol on carbon tetrachloride levels and hepatotoxicity after acute carbon tetrachloride poisoning.

To study the effect of an acute dose of ethanol on carbon tetrachloride (CCl4) concentration and hepatotoxicity, female rats received ethanol (2.5 ml/kg body wt.) either intragastrically or intraperitoneally following intragastric administration of CCl4 (1.5 ml/kg body wt.). Three hours after acute CCl4 intoxication there was a striking increase in CCl4 concentration in animals treated simultaneously with ethanol intragastrically compared to those receiving ethanol intraperitoneally. This increase was significant (P less than 0.05) and amounted to 211% for blood, 236% for liver and 405% for fat tissue, whereas animals treated with CCl4 alone showed CCl4 concentrations in the range between the two other experimental groups. Serum activities of glutamate oxalacetate transaminase, glutamate pyruvate transaminase and glutamate dehydrogenase were found to be considerably higher in animals treated with the combination of CCl4 and ethanol when compared to those receiving CCl4 alone, showing that ethanol given intraperitoneally or intragastrically enhances CCl4 hepatotoxicity. Since the intraperitoneal administration of ethanol led to a reduction rather than an increase in CCl4 concentration in the early phase of intoxication, additional mechanisms independent of actual levels of CCl4, such as direct effects of ethanol on the CCl4 metabolizing enzyme of the membrane of the endoplasmic reticulum, have to be implicated in the pathogenesis of the potentiation of CCl4 hepatotoxicity by ethanol.

Adipose Tissue↗
PubMed1983

Reductive oxygenation of carbon tetrachloride: trichloromethylperoxyl radical as a possible intermediate in the conversion of carbon tetrachloride to electrophilic chlorine.

Under aerobic conditions, rat liver microsomes convert carbon tetrachloride to an electrophilic form of chlorine that is trapped with 2,6-dimethylphenol to form 4-chloro-2,6-dimethylphenol. The mechanism of cytochrome P-450-catalyzed electrophilic chlorine formation from carbon tetrachloride was examined with structure-activity studies of electrophilic halogen formation and chemical and in vitro microsomal studies. 4-Chloro-2,6-dimethylphenol is not formed as a consequence of a reaction of 2,6-dimethylphenoxyl radical with carbon tetrachloride or carbon tetrachloride-induced lipid peroxyl radical formation. Only tetrahalomethanes were found to yield electrophilic halogens. The chemical oxidants hydrogen peroxide, cumene hydropheroxide, sodium periodate, and iodobenzene diacetate did not support electrophilic halogen formation from carbon tetrachloride, carbon tetrabromide, or hexachloroethane in microsomal studies. The addition of superoxide dismutase, catalase, sodium azide, or glutathione to microsomal incubations did not affect the rate of electrophilic chlorine formation, whereas Paraquat completely inhibited the reaction. The radical spin trap phenyl t-butyl nitrone (14 mM) completely inhibited electrophilic chlorine formation. The rate of electrophilic chlorine formation was highest at 2-5% atmospheric oxygen, whereas anaerobiosis completely inhibited electrophilic chlorine formation, and high oxygen tension impaired electrophilic chlorine formation. These results preclude direct oxidation of carbon tetrachloride or a reaction of superoxide anion radical with carbon tetrachloride as the initial step in electrophilic chlorine formation and suggest that the likely initial step is reductive dehalogenation of carbon tetrachloride to trichloromethyl radical which then traps oxygen to form trichloromethylperoxyl radical. Subsequent reaction of trichloromethyl peroxyl radical leads to electrophilic chlorine. These findings may have important implications concerning carbon tetrachloride-induced lipid peroxidation and carbon tetrachloride hepatotoxicity.

Aerobiosis↗