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PubMed1983

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.

Animals↗
PubMed1994

Chloroacetaldehyde-induced hepatocyte cytotoxicity. Mechanisms for cytoprotection.

2-Chloroacetaldehyde (CAA)-induced cytotoxicity in isolated hepatocytes was enhanced markedly if hepatocyte alcohol or aldehyde dehydrogenase was inhibited prior to CAA addition. Hepatocyte GSH depletion, ATP depletion and lipid peroxidation by CAA were also enhanced markedly. Furthermore, CAA was about 10- and 70-fold more cytotoxic than its oxidative or reductive metabolite chloroacetate or chloroethanol, respectively. Nutrients such as lactate, xylitol, sorbitol or glycerol, which increase cytosolic NADH levels, prevented CAA cytotoxicity in normal hepatocytes but further enhanced cytotoxicity toward alcohol dehydrogenase inactivated hepatocytes, suggesting that increased cytosolic NADH reduces CAA via alcohol dehydrogenase in normal hepatocytes but prevents CAA oxidation in alcohol dehydrogenase inactivated hepatocytes. However, increasing cytosolic NADH levels with ethanol or NADH-generating nutrients after CAA had been metabolized also prevented cytotoxicity and caused a partial ATP recovery, whereas oxidation of cytosolic NADH with pyruvate markedly increased cytotoxicity. This indicates that cytotoxic CAA concentrations cause oxidative stress and that ATP levels can be restored if cellular redox homeostasis is normalized with reductants. Furthermore, except for fructose, nutrients that did not increase NADH did not affect CAA-induced cytotoxicity. Fructose also caused a partial ATP recovery, and its protection was prevented by the glycolytic inhibitor fluoride. Hepatocytes isolated from fasted animals were 4- to 6-fold more susceptible to CAA-induced ATP depletion and cytotoxicity. No lipid peroxidation occurred at these lower CAA concentrations. Furthermore, all nutrients, including alanine, glutamine and glucose, prevented cytotoxicity toward hepatocytes isolated from fasted animals. The susceptibility of hepatocytes to CAA cytotoxicity, therefore, depends on both cellular redox homeostasis and cellular energy supply.

Acetaldehyde↗
PubMed1983

Characterization of IL-2-dependent cytotoxic T-cell clones. II. Cell-surface phenotypes, histochemical and ultrastructural properties.

This report examines the histochemical staining patterns, ultrastructure, and cell-surface phenotypes of six antigen-specific T-cell clones. Histochemical analyses indicated that all cell lines expressed alpha-napthyl butyrate esterase characteristic of the monocytic isoenzyme, intense napthol AS-D chloroacetate reactivity characteristic of granulocytes, and were negative for leucoperoxidase, alkaline phosphatase, and Sudan black. Only one clone stained weakly for acid phosphatase. The esterase staining patterns became evident in newly established cell lines after growth for only 1 week in interleukin 2-conditioned medium. Ultrastructurally, the outstanding feature was numerous membrane-bound granules containing a complex-appearing globular material. The cell-surface phenotypes of the lines as determined by protein A-sheep red blood cell rosetting and indirect immunofluorescence was Ly-5+, T200+, Qa-5-, MAC-1-, and Lyt-1+,2,3- for the helper line and Lyt-1-2,3+ for the five cytotoxic lines. By quantitative absorption analyses, low levels of Lyt-1 antigens were detected on all examined cytotoxic lines. The results strengthen the view that long-term T-cell lines can retain normal T-cell characteristics while also expressing markers that are either absent or in undetectable levels on uncultured T lymphocytes. The presence of the esterases may be associated with an expanded functional role in the T-cell lines.

Animals↗
PubMed1984

Alternative myelomonocytic differentiation of HL-60 reflects dual prospective potency of promyelocytes in human.

The permanent promyelocytic cell line HL-60 was subjected to stimulation with dimethyl sulfoxide (DMSO) and retinoic acid (RA), as well as 12-O-tetradecanoylphorbol-13-acetate (TPA) and lymphokine conditioned media for the induction of granulocytic or monocytic differentiation, respectively. Cells were investigated cytochemically using alpha-naphthylacetate esterase (acid esterase; AcE), naphthol AS-D chloroacetate esterase, and peroxidase reactions. In addition, the granulocyte or monocyte specific isoenzyme patterns of AcE as an intracytoplasmic property and the immunoreactivity to monoclonal antibodies recognizing granulocytes and monocytes (Ki-M2, Ki-M5) or monocytes alone (Ki-M1) were considered. The results indicated that HL-60 cell line bear the potency to evolve into granulocytes as well as monocytes. Additional studies performed on normal human bone marrow stained for AcE led to the conclusion that the myeloid cell line remains bipolar until the maturation stage of promyelocytes. Myelocytes being AcE positive only in 11.5 +/- 5.0 are heterogeneous and display the first indications of separated monocytic or granulocytic differentiation.

Antibodies, Monoclonal↗
PubMed1995

Reaction of glutathione with the electrophilic metabolites of 1,1-dichloroethylene.

1,1-Dichloroethylene (DCE) requires cytochrome P450-catalyzed bioactivation to electrophilic metabolites (1,1-dichloroethylene oxide, 2-chloroacetyl chloride and 2,2-dichloroacetaldehyde) to exert its cytotoxic effects. In this investigation, we examined the reactions of these metabolites with glutathione by spectroscopic and chromatographic techniques. In view of the extreme reactivity of 2-chloroacetyl chloride, primary reactions are likely to include alkylation of cytochrome P450, conjugation with GSH to give S-(2-chloroacetyl)-glutathione, or hydrolysis to give 2-chloroacetic acid. Our results showed conjugation of GSH with 1,1-dichloroethylene oxide, through formation of the mono- and di-glutathione adducts, 2-S-glutathionyl acetate and 2-(S-glutathionyl) acetyl glutathione, respectively. The observed equilibrium constant between the hydrate of 2,2-dichloroacetaldehyde and S-(2,2-dichloro-1-hydroxy)ethylglutathione was estimated from 1H-NMR experiments to be 14 +/- 2 M-1. Thus, 2,2-dichloroacetaldehyde is unlikely to make a significant contribution to GSH depletion as GSH concentrations above normal physiological levels would be necessary to form significant amounts of S-(2,2-dichloro-1-hydroxy)ethylglutathione. We also compared the formation of the glutathione conjugates in rat and mouse liver microsomes using 14C-DCE. The results demonstrated a species difference; the total metabolite production was 6-fold higher in microsomes from mice, compared with samples from rat. Production of DCE metabolites in hepatic microsomes from acetone-pretreated mice was 3-fold higher than those from untreated mice suggesting a role for P450 2E1 in DCE bioactivation. These results indicate that the epoxide is the major metabolite of DCE that is responsible for GSH depletion, suggesting that it may be involved in the hepatotoxicity evoked by DCE. Furthermore, this metabolite is formed to a greater extent in mouse than in rat liver microsomes and this difference may underlie the enhanced susceptibility found in the former species.

Acetaldehyde↗
PubMed1976

In vivo effects of some tertiary alkylaminoethyl esters with choline acetyltransferase inhibitory properties.

The tertiary nitrogen derivatives of two choline esters, chloroacetylcholine and acrylcholine, known to inhibit choline acetyltransferase (ChAc) in vitro, were tested for their effects in the whole animal, including peripheral and central cholinergic systems. These esters are N,N-dimethylaminoethyl chloroacetate (Cl-DMA) and N,N-dimethylaminoethyl acrylate (acryl-DMA). The peripheral preparations studied included a neuromuscular junction, a sympathetic ganglion and a postganglionic parasympathetic exocrine preparation. Both Cl-DMA and acryl-DMA blocked responses in these preparations when injected intravenously. The LD50 values for Cl-DMA and acryl-DMA were 640 mg/kg and 183 mg/kg, respectively. Cl-DMA and acryl-DMA were also able to inhibit brain ChAc when injected intravenously by 32% and 18.5%, respectively. The brain levels of acetylcholine (ACh) were significantly reduced by about 25% with Cl-DMA but not significantly with acryl-DMA when the animals were forced to exercise after injection. It is obvious that ChAc inhibition is not effective in decreasing ACh levels significantly under normal conditions.

Acetylcholine↗
PubMed1992

Aziridine-2-carboxylic acid. A reactive amino acid unit for a new class of cysteine proteinase inhibitors.

The three-membered ring of aziridine-2-carboxylic acid, which is susceptible to opening by nucleophiles, has been analyzed as a potential useful handle for the design of specific irreversible inhibitors of cysteine proteinases. For this thiol-reactive amino acid, an imino analogue of proline, a second-order rate constant of 17.07 M-1.s-1 for inactivation of papain was determined. Thus, the aziridine moiety proved to be remarkably more reactive than activated double bonds, e.g. N-ethylmaleimide, or halides such as alpha-iodopropionic acid or chloroacetic acid. Since it does not alkylate histidine under conditions in which quantitative alkylation occurs with N-ethyl-maleimide, it could represent an interesting reactive amino acid unit for the synthesis of a new class of irreversible inhibitors, at least in terms of specificity of the chemical reaction involved in the inactivation process.

Aziridines↗
PubMed1985

Determination of 2-(4-isobutylphenyl)propionic acid in bulk drug and compressed tablets by reversed-phase high-performance liquid chromatography.

A reversed-phase liquid chromatographic method was developed for 2-(4-isobutylphenyl)propionic acid (IBPP) in bulk drug and compressed tablets containing 100-600 mg of drug per tablet. The chromatographic system consists of a microparticulate octadecylsilica column and a mobile phase of aqueous acetonitrile buffered with chloroacetic acid. Whole tablets are disintegrated, and the IBPP dissolved in a solution of the internal standard in mobile phase. The resulting suspension is then centrifuged, and an aliquot of the supernatant chromatographed. This system separates IBPP from its analogues and degradation products in less than 10 min. Recovery of the drug from spiked placebo preparations was quantitative. Precision of the assay was 0.3 and 0.7%, relative standard deviation, for bulk drug and Motrin tablets, respectively.

Chemical Phenomena↗
PubMed1987

Nuclear segmentation, ultrastructure, and cytochemistry of blood cells from dogs with Pelger-Huët anomaly.

Nuclear segmentation, ultrastructural features and cytochemical staining reactions of blood cells from 7 dogs with the heterozygous form of Pelger-Huët (P-H) anomaly were investigated. Significant nuclear hyposegmentation of granulocytes, monocytes and megakaryocytes was found, indicating a common stem cell defect in the nuclear segmentation or lobulation process. Neutrophils and eosinophils from female P-H dogs lacked sex chromatin drumsticks. Other than the suggestion of nuclear hyposegmentation and the presence of coarse heterochromatin, no ultrastructural abnormalities were discerned. Cytochemical staining by a-naphthyl acetate esterase, alkaline phosphatase, naphthol ASD chloroacetate esterase, periodic acid-Schiff, peroxidase and Sudan black B techniques gave similar results for P-H and control dog leukocytes and platelets.

Animals↗
PubMed1992

Metabolism and lipoperoxidative activity of trichloroacetate and dichloroacetate in rats and mice.

Trichloroacetate (TCA) and dichloroacetate (DCA) have been shown to be hepatocarcinogenic in mice when administered in drinking water. However, DCA produces pathological effects in the liver that are much more severe than those observed following TCA treatment in both rats and mice. To identify potential mechanisms involved in the liver pathology, the biotransformation of TCA and DCA was investigated in male Fischer 344 rats and B6C3F1 mice. Rodents were administered 5, 20, or 100 mg/kg [14C]TCA or [14C]DCA as a single oral dose in water. Elimination was examined by counting radioactivity in urine, feces, exhaled air, and carcass. Blood concentration over time curves were constructed for both TCA and DCA at the 20 and 100 mg/kg doses. Analysis of the data reveals two significant differences in the systemic clearance of TCA relative to DCA. First, DCA was much more extensively metabolized than TCA. More than 50% of any single dose of TCA was excreted unchanged in the urine of both rats and mice. In contrast, less than 2% of any dose of DCA was recovered in the urine as the parent compound. Second, while the blood concentration over time curves for TCA were similar in rats and mice, the blood concentrations of DCA were markedly greater in rats compared to those in mice, both when DCA was administered and when DCA resulted from metabolism of TCA. DCA was detected in the urine of TCA-treated animals and chloroacetate was found in the urine of DCA-treated animals. These metabolic products would be expected to arise from a free radical-generating, reductive dechlorination pathway. To evaluate the ability of acute doses of TCA and DCA to elicit a lipoperoxidative response, additional groups of mice were administered 0, 100, 300, 1000, and 2000 mg/kg TCA or DCA and thiobarbituric acid-reactive substances (TBARS) measured in liver homogenates. Both TCA and DCA enhanced the formation of TBARS in a dose-dependent manner, thereby providing further evidence of a reductive metabolic pathway. DCA was found to be the more potent of the chlorinated acetates in increasing TBARS formation in the livers of both rats and mice. In view of these data, it appears that the more extensive metabolism and rapid rate of elimination of DCA relative to TCA and the more potent lipoperoxidative activity of DCA may be important factors in the pathological effects associated with DCA treatment.

Administration, Oral↗
PubMed1976

Clones of Friend leukemia cells: differences in karyotypes and responsiveness to inducers of differentiation.

Several clones of Friend leukemia cells have been established which differ in their chromosome composition. These cells also vary with regard to their responsiveness to DMSO, whereas all are responsive to butyric acid. Hence, there appears to be independent assortment of the ability of a cell line to respond to DMSO and to butyric acid, suggesting a different mechanism of action for each agent. Further, individual Friend cells possess the ability to simultaneously contain chloroacetate esterase and heme--two biochemical properties which have previously been believed to be mutually exclusive.

Acetamides↗
PubMed1994

Systemic mast cell disease presenting with peripheral blood eosinophilia.

Patients with mast cell disease most frequently present with skin lesions (urticaria pigmentosa), with systemic involvement in many cases. However, a small subset of patients with systemic mast cell disease lacks skin lesions and, in these patients the correct diagnosis may be difficult to establish. Patients with systemic mast cell disease commonly have hematologic abnormalities, including eosinophilia in up to 20% of cases, but isolated eosinophilia has been reported rarely. We describe an 82-year-old woman who was admitted to Rhode Island Hospital for coronary artery disease and unstable angina. Incidentally, an absolute eosinophil count of 7.84 x 10(9)/L (normal, < 0.45 x 10(9)/L) was detected with moderate thrombocytopenia and mild anemia. Review of earlier records revealed that absolute eosinophilia had been present for approximately 4 months, initially without other hematologic abnormalities. Clinical work-up showed left upper quadrant tenderness. No skin lesions were identified. Bone marrow core biopsy revealed paratrabecular, perivascular, and medullary mast cell aggregates with eosinophils, suggestive of mast cell disease. At autopsy the diagnosis was confirmed. Mast cell aggregates were found in the liver, spleen, lymph nodes, and bone marrow, and chloroacetate esterase stain highlighted mast cell granules. The bone marrow was also hypercellular with granulocytic and eosinophilic hyperplasia, suggestive of a poorly defined myeloproliferative disorder. Patients with systemic mast cell disease initially may present with peripheral eosinophilia. Clinical suspicion of the diagnosis facilitates proper handling of the bone marrow core biopsy specimen to allow the demonstration of mast cell granules.

Aged↗
PubMed1986

Direct in vivo evidence for mast cell degranulation during allergen-induced reactions in man.

There is little or no direct in vivo evidence in man to support the involvement of mast cell-mediator release in the pathogenesis of immediate allergic reactions. We have performed a within-subject controlled study to determine the changes that occur in nasal mast cells during allergen-induced rhinitis. Twelve subjects with asymptomatic rhinitis were studied. Nasal biopsy specimens were obtained from each subject after a control solution (isotonic saline, 0.9% w/v) had been nebulized into one nostril and allergen solution (freeze-dried allergen extract reconstituted with isotonic saline) into the other. The tissues obtained were fixed in Carnoy's solution and stained with the alpha-naphthol AS-D chloroacetate esterase reaction (N AS-D CA ER). Mast cells were counted under light microscopy in the epithelium and lamina propria, and the integrity of each cell was assessed. No significant differences were found in the number of epithelial or lamina propria mast cells in biopsy specimens obtained after saline or allergen administration. However, the number of degranulated mast cells after allergen provocation (89%) was significantly greater than after instillation of control solution (15%) (p = 0.003). Changes of mast cell degranulation after allergen provocation were confirmed by electron microscopy. In six nonatopic, control subjects without rhinitis, there was no significant difference between the percentages of degranulated mast cells after allergen provocation (25.8%) and instillation of saline (24.3%). This study provides direct in vivo evidence for allergen-induced mast cell activation in man.

Adult↗
PubMed1982

Cell surface antigen phenotypes and enzyme expression patterns of two murine T-cell lymphomas derived from early and/or mature thymus cells.

A number of cell surface markers (T200, ThB, Thy1, Lyt1 and Lyt2 and a glycolipid) and enzymes (ATP-ase, acid phosphatase, beta-glucuronidase, 5'-nucleotidase, non-specific esterase, ANAE and chloroacetate esterase) were determined for two murine T-cell lymphomas: the DBA/2-strain-derived SL2 with a phenotype close to that of a mature thymocyte and the GRS-strain-derived GSRL13 with a phenotype of a more primitive thymocyte. While the pattern of expression of the enzymes was similar for SL2 and GRSL13 and as such indistinguishable from that of the majority of thymus cells, the pattern of cell surface antigen expression was clearly different. GRSL12 cells express the ThB antigen and a glycolipid antigen detectable with monoclonal antibody 30-H11, but not Lyt1 and Lyt2 antigens. SL2 cells, however, do not express ThB and the glycolipid antigen, but do express Lyt1 and Lyt2.

Animals↗
PubMed1987

A characteristic CFU-GM growth pattern in acute promyelocytic leukemia.

Bone marrow and/or peripheral blood cells from 12 patients with acute promyelocytic leukemia (APL) were cultured in soft agar or methylcellulose in the presence of 15% human placental conditioned medium as a source of colony stimulating factor. Buffy coat cells, taken from ten patients when APL was diagnosed, produced a growth pattern in soft agar that was characterized by a high incidence of small, relatively uniform clusters of promyelocytes, which, when stained in situ, reacted strongly with myeloperoxidase, Sudan black B and chloroacetate esterase. In six cases, the leukemic origin of the cluster forming cells was demonstrated by the presence of the t(15;17) in these cells. During periods of complete remission the small clusters were replaced by larger and more diverse aggregates which had a normal karyotype. At relapse the small cluster growth pattern returned. The growth pattern of small clusters is more commonly associated with APL than with other types of acute myeloid leukemia.

Adult↗
PubMed1988

Establishment of an immature mast cell line from a patient with mast cell leukemia.

A cell line showing many characteristics of immature mast cells has been established from the peripheral blood of a patient with mast cell leukemia. Cultured cells contain low levels of histamine, are stained metachromatically by toluidine blue, and contain chloroacetate esterase, aminocaproate esterase and tryptase activities. The cells lack T and B lymphocyte, as well as myeloid cell markers, and do not possess IgE receptors. Solid tumors of metachromatically positive cells have been successfully induced and serially passed in nude mice using 5-azacytidine transformed cells. This cell line may be useful for future studies of mast cells and their constituents.

Animals↗
PubMed1990

Philadelphia chromosome-negative acute hematopoietic malignancy: ultrastructural, cytochemical and immunocytochemical evidence of mast cell and basophil differentiation.

We describe a patient with fever and multiple osteolytic bone lesions accompanied by hypercalcemia, a duodenal ulcer, anemia, and thrombocytopenia. Bone marrow showed a dense infiltration by abnormal cells characterized by small basophil granula, erythrophagocytosis and nuclear atypia. These cells were positive for toluidine blue and partly for myeloperoxidase and chloroacetate esterase, expressed myeloid differentiation markers, and exhibited multiple numerical and structural chromosome aberrations. Molecular genetic analysis showed no breakpoint cluster region rearrangement. Electron microscopy demonstrated granula both of basophil and mast cell type. Concluding, in this patient an acute hematopoietic malignancy with many features of malignant mastocytosis but also with signs of a basophil differentiation. This is further support for a hematopoietic stem cell origin of human mast cells.

Adult↗
PubMed1993

B-lymphoid/myeloid stem cell origin in Ph-positive acute leukemia with myeloid markers.

We report two cases of Philadelphia chromosome (Ph)-positive acute leukemia with definite myeloid markers. Ph was the sole chromosomal abnormality at presentation, and neither eosinophilia, basophilia, thrombocytosis nor hepatosplenomegaly was present. In both cases, Ph+ myeloblasts showed positive stain for myeloperoxidase and naphthol ASD chloroacetate esterase, which fulfilled the FAB criteria of acute myelogenous leukemia (AML). Ph+ myeloblasts co-expressed myeloid and B-lymphoid antigens (CD10, CD13, CD19 and CD33). In case 1, myeloblasts rearranged M-BCR, and the expression of M-BCR/ABL chimeric RNA was demonstrated by using the reverse transcription polymerase chain reaction (RT-PCR). They also clonally rearranged IGH. Ph clone disappeared on cytogenetic analysis in remission, and granulocytes in remission did not have rearranged M-BCR. In case 2, morphocytochemically distinct myeloid and lymphoid blast populations were seen. Myeloblasts and lymphoblasts were enriched > 96% as CD19-/CD33+ and CD19+/CD33- populations, respectively. Both of them possessed the identical rearrangement of IGH and M-BCR, indicating a common leukemic progenitor cell origin. Furthermore, m-BCR/ABL was detected in addition to M-BCR/ABL on RT-PCR. Accordingly, both cases were diagnosed as de novo Ph+ acute leukemia rather than as chronic myelogenous leukemia in blastic crisis. Their mixed B-lymphoid/myeloid characteristics strongly suggest that so-called 'Ph+ AML' is derived from Ph+ myeloid/B-lymphoid stem cells.

Adolescent↗