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Dolores B. Njoku - One of the best experts on this subject based on the ideXlab platform.
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Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS One 2013
2016Co-Authors: Noel R. Rose, Dolores B. Njoku, Monica V. Talor, Joonhee Cho, Lina Kim, Monica Vladut TalorAbstract:Background and Aims: Immune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17b-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. Methods: To model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with Trifluoroacetyl Chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. Results: BALB/c females developed more severe hepatitis (p,0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p,0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p,0.001
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Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS One 2013
2016Co-Authors: Joonhee Cho, Noel R. Rose, Lina Kim, Monica Vladut Talor, Dolores B. NjokuAbstract:Background and Aims: Immune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17b-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. Methods: To model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with Trifluoroacetyl Chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. Results: BALB/c females developed more severe hepatitis (p,0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p,0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p,0.001) and females (p,0.05). Splenocytes cultured from female mice exhibited fewer Tregs (p,0.01) and higher IL-1b (p,0.01) and IL-6 (p,0.05) than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor a-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-
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Sex Bias in Experimental Immune-Mediated, Drug-Induced Liver Injury in BALB/c Mice: Suggested Roles for Tregs, Estrogen, and IL-6
PloS one, 2013Co-Authors: Joonhee Cho, Noel R. Rose, Monica V. Talor, Lina Kim, Dolores B. NjokuAbstract:Background and Aims Immune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. Methods To model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with Trifluoroacetyl Chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. Results BALB/c females developed more severe hepatitis (p
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Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury.
European journal of immunology, 2009Co-Authors: Dolores B. Njoku, Nicole D. Washington, Jenelle L. Mellerson, Monica V. Talor, Rajni Sharma, Noel R. RoseAbstract:The pathogenesis of immune-mediated drug-induced liver injury (DILI) following halogenated anesthetics, carbamazepine or alcohol has not been fully elucidated. Detecting cytochrome P450 2E1 (CYP2E1) IgG4 auto-antibodies in anesthetic DILI patients suggests a role for IL-4 in this hapten-mediated process. We investigated IL-4-mediated mechanisms using our model of experimental DILI induced by immunizing BALB/c (WT) and IL-4(-/-) (KO) mice with S100 liver proteins covalently modified by a Trifluoroacetyl Chloride (TFA) hapten formed following halogenated anesthetic metabolism by CYP2E1. WT mice developed more hepatitis, TFA and S100 antibodies (p
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Desflurane hepatitis associated with hapten and autoantigen-specific IgG4 antibodies.
Anesthesia and analgesia, 2007Co-Authors: James S. Anderson, Noel R. Rose, Jackie L. Martin, Edmond I. Eger, Dolores B. NjokuAbstract:BACKGROUND: Three cases of drug-induced liver injury (DILI) have been reported after desflurane anesthesia. However, no previous reports have detected serum autoantibodies such as that reported with DILI from halothane or isoflurane. METHODS AND RESULTS: We describe the first documentation of cytochrome P450 2E1 IgG4 autoantibodies, as well as 58 kDa endoplasmic reticulum protein and Trifluoroacetyl Chloride hapten-specific IgG4 antibodies, in a patient who developed DILI after desflurane anesthesia. CONCLUSIONS: These findings suggest that allergic and autoimmune mechanisms have critical roles in the development of desflurane DILI.
A. Jay Gandolfi - One of the best experts on this subject based on the ideXlab platform.
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Kupffer cells from halothane-exposed guinea pigs carry Trifluoroacetylated protein adducts
Toxicology, 1997Co-Authors: Sylvia M. Furst, Dennis Luedke, A. Jay GandolfiAbstract:Abstract The anesthetic, halothane, is bioactivated by the liver cytochrome P450 system to Trifluoroacetyl-Chloride, which can readily acylate liver protein. Covalent binding of the Trifluoroacetyl moiety may result in hapten formation leading to the induction of an immune response and ultimately halothane hepatitis. In this study the presence of Trifluoroacetylated-protein adducts in Kupffer cells was investigated to learn how the immune system might come in contact with the proteins. Guinea pigs were exposed to 1.0% halothane, 40% oxygen for 4 h. Kupffer cells were isolated on days 1 through 9 post-exposure, by liver perfusion and purification by elutriation. Using gel electrophoresis and Western blotting techniques, it has been demonstrated that Kupffer cells obtained from halothane-treated guinea pigs, do carry Trifluoroacetyl-protein adducts as recognized by an anti-Trifluoroacetyl-rabbit serum albumin antibody. Apparent molecular weights of polypeptides bound by Trifluoroacetyl were of a wide range, 25–152 kDa. Bands were most prominent in the larger Kupffer cells with more appearing at lower molecular weights. Trifluoroacetyl-protein adducts were not detected in lung, spleen, lymph node or peripheral blood macrophages. This work suggests a role for Kupffer cells in the presentation of altered proteins in the liver to cells of the immune system.
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Glutathione-S-transferase is a target for covalent modification by a halothane reactive intermediate in the guinea pig liver.
Toxicology, 1994Co-Authors: Alan P. Brown, A. Jay GandolfiAbstract:Abstract The anesthetic halothane is bioactivated by the liver cytochrome P450 system to the reactive intermediate, Trifluoroacetyl Chloride, which can acylate liver protein. Cytosolic glutathione-S-transferase (GST) was identified as a major target for protein adduct formation in guinea pig liver slices exposed to halothane. To determine if GST is also a target in vivo, male Hartley guinea pigs were exposed to 1% halothane in 40% O2 for 4 h. At 10 h post exposure, livers were removed and microsomal and cytosolic fractions prepared. Past studies have shown these conditions resulted in maximal covalent binding of halothane intermediates to hepatic protein. Protein was isolated by ethanol precipitation and washed with trichloroacetic acid to remove unbound metabolites. Cytosolic GST was isolated by gel filtration and S-hexyl-glutathione affinity chromatography to electrophoretic purity. Protein adducts were quantified using a covalently bound fluorine assay. Covalent binding of a halothane intermediate to cytosolic and microsomal protein was determined as 2.0 ± 0.4 and 13.2 ± 2.3 nmol F/mg protein, respectively. Liver glutathione depletion by buthionine sulfoximine pretreatment produced an increase in covalent binding only to cytosolic proteins (3.3 ± 0.4 nmol F/mg protein). Adduct formation to cytosolic GST was determined to be 4.7 ± 1.6 nmol F/mg protein. Glutathione-S-transferase is a target for covalent modification in the liver following an inhalation exposure to halothane.
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Formation and identification of protein adducts to cytosolic proteins in guinea pig liver slices exposed to halothane.
Toxicology, 1992Co-Authors: Alan P. Brown, A. Jay Gandolfi, Kenneth L. Hastings, Daniel C. Liebler, Klaus BrendelAbstract:Abstract The anesthetic halothane can be bioactivated to the reactive intermediate, Trifluoroacetyl Chloride, which can covalently bind to liver protein. The product of this reaction is Trifluoroacetyl-N-ϵ-lysine which can act as a foreign epitope in altering both protein immunogenicity and antigenicity. An in vitro liver slice system was used to study the formation of protein adducts following exposure to halothane. Liver slices (30–35 mg wet weight, 250–300 μm thick) from adult male Hartley guinea pigs (600–800 g) were exposed to [14C]galothane (0.6–0.9 μCi, 1.0–1.7 mM) in 95% O2/5% CO2 for 1, 6 and 12 h. The slices were homogenized and subcellular fractions prepared. Proteins were resolved by electrophoresis and bound radioactivity was detected by scintillation counting and autoradiography. Greater than 80% of detectable radioactivity to whole liver cell protein was localized in the 20–30-kDa range and increased in a linear fashion over the 12-h incubation period. Covalent binding was localized to two proteins of 27 kDa and 26 kDa present in the cytosolic compartment. Purification followed by N-terminal amino acid sequence analysis of the 27-kDa protein has identified it to be homologous glutathione-S-transferaseb. This cytosolic protein appears to be the major target for Trifluoroacetylation in liver slices exposed to halothane.
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Generation and detection of neoantigens in guinea pig lever slices incubated with halothane
International journal of immunopharmacology, 1991Co-Authors: Alan P. Brown, Kenneth L. Hastings, A. Jay GandolfiAbstract:Abstract The volatile anesthetic halothane can be biotransformed by the hepatic cytochrome P-450 system to produce a reactive intermediate, Trifluoroacetyl Chloride, capable of covalently binding to liver proteins. The product of this reaction, the Trifluoroacetyl lysinyl moiety, can act as an epitope to alter protein antigenicity. An in vitro system has been developed to produce halothane induced neoantigens and to study conditions for formation in the liver. Liver slices, capable of halothane biotransformation, provide a viable means for mechanistic studies. Liver slices (1 cm diameter, 300 μm thick) from male Hartley guinea pigs (600–800 g) were exposed to either 1.0 or 1.7 nM halothane (media concentration) in 95% O 2 /5% CO 2 for 12 h. Covalent binding was determined using 14 C-halothane. Neoantigens were detected by Western immunoblot analysis using rabbit anti-Trifluoroacetylated albumin antiserum. Covalent binding was detected by 1 h of incubation and increased linearly through 12 h (20.7 – 48.5 nmole equiv/mg protein). Covalent binding preceded and correlated with the appearance of neoantigens. By 12 h of incubation, five neoantigens were seen with molecular weights ranging from 51 to 97 kD. These neoantigens have molecular weights similar to those seen in vivo . Liver slices exposed to deuterated halothane, which is oxidatively metabolized to a lower extent, did not develop neoantigens. This in vitro model system can be used to examine the mechanism for covalent binding and neoantigen production in the hepatocyte.
Ph. Mirabel - One of the best experts on this subject based on the ideXlab platform.
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kinetics of mass transfer of carbonyl fluoride Trifluoroacetyl fluoride and Trifluoroacetyl Chloride at the air water interface
The Journal of Physical Chemistry, 1994Co-Authors: Ch. George, J. Y. Saison, J. L. Ponche, Ph. MirabelAbstract:The heterogeneous chemistry, on aqueous surfaces, of a series of acid halides, COF[sub 2], CF[sub 3]COF, and CF[sub 3]-COCl, was studied. The technique used consists of a low-pressure flow tube reactor in which a stream of monodisperse droplets interacts with the gaseous acid halide. The experiments, which were performed as a function of the initial pH of the droplets, temperature, and gas/liquid interaction time, yield low uptake coefficients in the range 5 [times] 10[sup [minus]4] to 5 [times] 10[sup [minus]3] and allow estimation of the product H[radical]k, where H is the Henry's law constant and k is the hydrolysis rate constant. The values reported here are 60, 60, and 350 M[center dot]atm[sup [minus]1] s[sup [minus][1/2]] for CF[sub 3]COCl, CF[sub 3]COF, and COF[sub 2], respectively, at 273 K. Separate values of H and k are also reported. The results show slightly different behavior between the Chloride and the fluorides as a function of temperature. This study shows Henry's law and hydrolysis rate constants large enough that heterogeneous reactions on aqueous surfaces will limit the residence time of these species in the atmosphere. 25 refs., 8 figs., 1 tab.
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Kinetics of mass transfer of carbonyl fluoride, Trifluoroacetyl fluoride, and Trifluoroacetyl Chloride at the air/water interface
The Journal of Physical Chemistry, 1994Co-Authors: Ch. George, J. Y. Saison, J. L. Ponche, Ph. MirabelAbstract:The heterogeneous chemistry, on aqueous surfaces, of a series of acid halides, COF[sub 2], CF[sub 3]COF, and CF[sub 3]-COCl, was studied. The technique used consists of a low-pressure flow tube reactor in which a stream of monodisperse droplets interacts with the gaseous acid halide. The experiments, which were performed as a function of the initial pH of the droplets, temperature, and gas/liquid interaction time, yield low uptake coefficients in the range 5 [times] 10[sup [minus]4] to 5 [times] 10[sup [minus]3] and allow estimation of the product H[radical]k, where H is the Henry's law constant and k is the hydrolysis rate constant. The values reported here are 60, 60, and 350 M[center dot]atm[sup [minus]1] s[sup [minus][1/2]] for CF[sub 3]COCl, CF[sub 3]COF, and COF[sub 2], respectively, at 273 K. Separate values of H and k are also reported. The results show slightly different behavior between the Chloride and the fluorides as a function of temperature. This study shows Henry's law and hydrolysis rate constants large enough that heterogeneous reactions on aqueous surfaces will limit the residence time of these species in the atmosphere. 25 refs., 8 figs., 1 tab.
Noel R. Rose - One of the best experts on this subject based on the ideXlab platform.
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Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS One 2013
2016Co-Authors: Noel R. Rose, Dolores B. Njoku, Monica V. Talor, Joonhee Cho, Lina Kim, Monica Vladut TalorAbstract:Background and Aims: Immune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17b-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. Methods: To model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with Trifluoroacetyl Chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. Results: BALB/c females developed more severe hepatitis (p,0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p,0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p,0.001
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Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6. PLoS One 2013
2016Co-Authors: Joonhee Cho, Noel R. Rose, Lina Kim, Monica Vladut Talor, Dolores B. NjokuAbstract:Background and Aims: Immune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17b-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. Methods: To model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with Trifluoroacetyl Chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. Results: BALB/c females developed more severe hepatitis (p,0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p,0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p,0.001) and females (p,0.05). Splenocytes cultured from female mice exhibited fewer Tregs (p,0.01) and higher IL-1b (p,0.01) and IL-6 (p,0.05) than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor a-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-
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Sex Bias in Experimental Immune-Mediated, Drug-Induced Liver Injury in BALB/c Mice: Suggested Roles for Tregs, Estrogen, and IL-6
PloS one, 2013Co-Authors: Joonhee Cho, Noel R. Rose, Monica V. Talor, Lina Kim, Dolores B. NjokuAbstract:Background and Aims Immune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. Methods To model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with Trifluoroacetyl Chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. Results BALB/c females developed more severe hepatitis (p
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Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury.
European journal of immunology, 2009Co-Authors: Dolores B. Njoku, Nicole D. Washington, Jenelle L. Mellerson, Monica V. Talor, Rajni Sharma, Noel R. RoseAbstract:The pathogenesis of immune-mediated drug-induced liver injury (DILI) following halogenated anesthetics, carbamazepine or alcohol has not been fully elucidated. Detecting cytochrome P450 2E1 (CYP2E1) IgG4 auto-antibodies in anesthetic DILI patients suggests a role for IL-4 in this hapten-mediated process. We investigated IL-4-mediated mechanisms using our model of experimental DILI induced by immunizing BALB/c (WT) and IL-4(-/-) (KO) mice with S100 liver proteins covalently modified by a Trifluoroacetyl Chloride (TFA) hapten formed following halogenated anesthetic metabolism by CYP2E1. WT mice developed more hepatitis, TFA and S100 antibodies (p
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Desflurane hepatitis associated with hapten and autoantigen-specific IgG4 antibodies.
Anesthesia and analgesia, 2007Co-Authors: James S. Anderson, Noel R. Rose, Jackie L. Martin, Edmond I. Eger, Dolores B. NjokuAbstract:BACKGROUND: Three cases of drug-induced liver injury (DILI) have been reported after desflurane anesthesia. However, no previous reports have detected serum autoantibodies such as that reported with DILI from halothane or isoflurane. METHODS AND RESULTS: We describe the first documentation of cytochrome P450 2E1 IgG4 autoantibodies, as well as 58 kDa endoplasmic reticulum protein and Trifluoroacetyl Chloride hapten-specific IgG4 antibodies, in a patient who developed DILI after desflurane anesthesia. CONCLUSIONS: These findings suggest that allergic and autoimmune mechanisms have critical roles in the development of desflurane DILI.
Len Taing - One of the best experts on this subject based on the ideXlab platform.
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Vibrational Analysis of the Ground States of Trifluoroacetyl Fluoride and Trifluoroacetyl Chloride
The Journal of Physical Chemistry A, 2000Co-Authors: Gary D. Bent, Essaid Zerrad, Gary W. Trucks, Kenneth B. Wiberg, Len TaingAbstract:The vibrational frequencies, normal modes of vibration, and force constants of CF3COF and CF3COCl are calculated using the MP2/6-31G(d‘) method. Our calculations agree with those of Pacansky et al. in showing that the values of the ν6, ν7, ν8, ν12, and ν13 experimental frequencies of CF3COF need to be reassigned. Our calculations also show that the same experimental frequencies in CF3COCl need to be reassigned. The calculated force constants are improved by fitting them to the reassigned experimental vibrations. The simple descriptions of vibrational motion previously given are shown to be inaccurate for most vibrations.
