Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene, a ubiquitous environmental pollutant, is known to cause leukemia and aplastic anemia in humans and hematotoxicity and myelotoxicity in rodents. Toxicity is thought to be exerted through oxidative metabolites formed in the liver, primarily via pathways mediated by cytochrome P450 2E1 (CYP2E1). Phenol, hydroquinone and trans-trans-muconaldehyde have all been hypothesized to be involved in benzene-induced toxicity. Recent reports indicate that benzene oxide is produced in vitro and in vivo and may be sufficiently stable to reach the bone marrow. Our goal was to improve existing mathematical models of microsomal benzene metabolism by including time course data for benzene oxide, by obtaining better parameter estimates and by determining if enzymes other than CYP2E1 are involved. Microsomes from male B6C3F1 mice and F344 rats were incubated with [(14)C]benzene (14 microM), [(14)C]phenol (303 microM) and [(14)C]hydroquinone (8 microM). Benzene and phenol were also incubated with mouse microsomes in the presence of trans-dichloroethylene, a CYP2E1 inhibitor, and benzene was incubated with trichloropropene oxide, an epoxide hydrolase inhibitor. These experiments did not indicate significant contributions of enzymes other than CYP2E1. Mathematical model parameters were fitted to rodent data and the model was validated by predicting human data. Model simulations predicted the qualitative behavior of three human time course data sets and explained up to 81% of the total variation in data from incubations of benzene for 16 min with microsomes from nine human individuals. While model predictions did deviate systematically from the data for benzene oxide and trihydroxybenzene, overall model performance in predicting the human data was good. The model should be useful in quantifying human risk due to benzene exposure and explicitly accounts for interindividual variation in CYP2E1 activity.
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PMID:Use of a mathematical model of rodent in vitro benzene metabolism to predict human in vitro metabolism data. 1042

Benzene is an occupational hazard and environmental toxicant found in cigarette smoke, gasoline, and the chemical industry. The major health concern associated with benzene exposure is leukemia. Studies using microsomal preparations from human, mouse, rabbit, and rat to determine species differences in the metabolism of benzene to phenol, hydroquinone and catechol, indicate that the rat is most similar, both quantitatively and qualitatively, to the human in pulmonary microsomal metabolism of benzene. With hepatic microsomes, rat is most similar to human in metabolite formation at the two lower concentrations examined (24 and 200 microM), while at the two higher concentrations (700 and 1000 microM) mouse is most similar in phenol formation. In all species, the enzyme system responsible for benzene metabolism approached saturation in hepatic microsomes but not in pulmonary microsomes. In pulmonary microsomes from mouse, rat, and human, phenol appeared to competitively inhibit benzene metabolism resulting in a greater proportion of phenol being converted to hydroquinone when the benzene concentration increased. The opposite effect was seen in hepatic microsomes. These findings support the hypothesis that the lung plays an important role in benzene metabolism, and therefore, toxicity.
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PMID:Species comparison of hepatic and pulmonary metabolism of benzene. 1064 21

Using two-dimensional electrophoresis we investigated the effect of 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT; induction with 1 mM ALA for 4 h followed by blue light dose of 18 J/cm2) on the protein expression in HL60 leukemia cells. ALA-PDT resulted in extensive qualitative and quantitative changes in the protein pattern of HL60 cell lysates. Of more than 1350 protein spots recognized on the protein maps of ALA-induced cells, seven proteins were enhanced and 17 suppressed following irradiation. Three of these, calreticulin precursor, p58 microsomal protein (ERp57) and protein disulfide isomerase (p55) have been identified by matrix-assisted laser desorption and ionization-mass spectrometry and the pI/molecular weight parameters of the affected proteins were estimated by computer analysis. The findings suggest participation of endoplasmic reticulum Ca(2+)-binding chaperones and/or Ca2+ signaling in ALA-PDT mediated cytotoxicity.
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PMID:Protein changes in HL60 leukemia cells associated with 5-aminolevulinic acid-based photodynamic therapy. Early effects on endoplasmic reticulum chaperones. 1091 24

We have previously shown that the two membrane bound enzymes leukotriene C synthase and microsomal glutathione S-transferase interact in vitro and in vivo. Rat basophilic leukemia cells and murine mastocytoma cells, two well-known sources of leukotriene C synthase, both expressed microsomal glutathione S-transferase as determined by Western blot analyses. Several human tissues were found to contain both leukotriene C synthase and microsomal glutathione S-transferase mRNA. These data suggest that the interaction may be physiologically important. To study this further, expression vectors encoding the two enzymes were cotransfected into mammalian cells and the subcellular localization of the enzymes was determined by indirect immunofluorescence using confocal laser scanning microscopy. The results showed that leukotriene C synthase and microsomal glutathione S-transferase were both localized on the nuclear envelope and adjacent parts of the endoplasmic reticulum. Image overlay demonstrated virtually identical localization. We also observed that coexpression substantially reduced the catalytic activity of each enzyme suggesting that a mechanism involving protein-protein interaction may contribute to the regulation of LTC4 production.
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PMID:Colocalization of leukotriene C synthase and microsomal glutathione S-transferase elucidated by indirect immunofluorescence analysis. 1103 37

Benzene is an occupational hazard and environmental toxicant found in cigarette smoke, gasoline, and the chemical industry. The major health concern associated with benzene exposure is leukemia. The toxic effects of benzene are dependent on its metabolism by the cytochrome P450 enzyme system. Previous research has identified CYP2E1 as the primary P450 isozyme responsible for benzene metabolism at low concentrations, whereas CYP2B1 is involved at higher concentrations. Our studies using microsomal preparations from human, mouse, and rat indicate that CYP2E1 is the P450 isozyme primarily responsible for benzene metabolism in lung and in liver. CYP2B isozymes have little involvement in benzene metabolism by either lung or liver. Our results also indicate that isozymes of the CYP2F subfamily may play a role in benzene metabolism by lung.
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PMID:Cytochromes P450 involved with benzene metabolism in hepatic and pulmonary microsomes. 1108 83

Nicotinic acid-adenine dinucleotide phosphate (NAADP), a molecule derived from beta-NADP, has been shown to promote intracellular calcium release in sea urchin eggs. However, there is little information regarding the role of NAADP in the regulation of intracellular calcium fluxes in mammalian cells. We found recently that several mammalian tissues have a high capacity for NAADP synthesis, as assessed by sea urchin egg bioassay. To determine the functional significance of NAADP production by mammalian tissues, we sought to determine whether NAADP is capable of inducing calcium release from microsomes prepared from cultured cells. We found that NAADP, but not beta-NADP, activates a specific microsomal calcium release system in mesangial cells isolated from rat kidney; NAADP was without effect in renal tubular epithelial cells. NAADP-induced calcium release is not affected by inhibitors of the inositol 1,4,5-trisphosphate or ryanodine channels. However, NAADP-elicited calcium release was inhibited by L-type calcium channel blockers and by alkaline phosphatase treatment of NAADP. NAADP also promotes specific microsomal calcium release in rat vascular smooth muscle cells, cardiac myocytes, fibroblasts and a human leukaemia cell line, indicating that the capacity for NAADP-induced calcium release is widespread in mammalian cells. We propose that NAADP may be an important regulator of intracellular calcium in many mammalian tissues.
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PMID:Nicotinic acid-adenine dinucleotide phosphate (NAADP) elicits specific microsomal Ca2+ release from mammalian cells. 1117 Oct 49

Benzene (C6H6) is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. Benzene increases the incidence of leukemia in humans when they are exposed to high doses for extended periods; however, leukemia risks in humans at low exposures are uncertain. The exposure-dose-response relationship of benzene in humans is expected to be nonlinear because benzene undergoes a series of metabolic transformations, detoxifying and activating, in the liver, resulting in multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites, benzene oxide, phe nol, and hydroquinone. As many parameter values as possible were taken from the literature; in particular, metabolic parameters obtained from in vitro studies with mouse liver were used since comparable parameters are also available for humans. Parameters estimated by fitting the model to published data were first-order rate constants for pathways lacking in vitro data and the concentrations of microsomal and cytosolic protein, which effectively alter overall enzyme activity. The model was constrained by using the in vitro metabolic parameters (maximum velocities, first-order rate constants, and saturation parameters), and data from multiple laboratories and experiments were used. Despite these constraints and sources of variability, the model simulations matched the data reasonably well in most cases, showing that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry. Therefore in vitro metabolic constants for humans can subsequently be extrapolated to predict the dosimetry of benzene and its metabolites in humans. This will allow us to better estimate the risks of adverse effects from low-level benzene exposures.
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PMID:Physiologically based pharmacokinetic modeling of benzene metabolism in mice through extrapolation from in vitro to in vivo. 1128 18

Our previous data have shown some differences in electrophoretic characteristics of proteins from cellular fractions (nuclear, mitochondrial, microsomal and cytosolic) isolated from peripheral blood mononuclear cells of B-cell chronic lymphocytic leukemia (B-CLL), acute lymphoblastic leukemia (ALL) patients and healthy donors. The main differences were found in electrophoretic patterns of nuclear proteins from normal and leukemia cells, especially in the nuclear mass regions of 36-52, 58-85, and 120-180 kDa. Electrophoretically-specific nuclear non-histone protein in the molecular mass zone 44/46 kDa of cells obtained from the peripheral blood of a B-CLL patient was used to produce rabbit polyclonal antiserum. SDS-polyacrylamide gel electrophoresis as well as immunological techniques (Western blot and immunocytochemistry) indicate that the nuclear protein with a molecular mass of 44/46 kDa is specifically expressed in mononuclear cells from B-CLL patients. The expression of this particular nuclear protein seems to correlate with the progression of the leukemia.
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PMID:Altered expression of nuclear non-histone protein (p44/46) in different stages of B-chronic lymphocytic leukemia. 1137 81

Epidemiology studies show increased leukemia mortality among styrene butadiene rubber (SBR) workers but not among butadiene monomer production employees. A detailed review of the SBR manufacturing process indicates that sodium dimethyldithiocarbamate (DMDTC) introduced into the SBR manufacturing process for a period in the 1950s coincides with increased leukemia mortality. Using the Computer-Optimized Molecular Parametric Analysis of Chemical Toxicity (COMPACT), we assessed the enzyme (cytochrome P450) substrate specificity of an olefin series including 1,3-butadiene (BD) and also modeled its interaction with DMDTC. These analyses showed correlation of a structural/electronic parameter--the COMPACT radius--with the presence or absence of cytogenetic activity and also found that DMDTC would inhibit the oxidative metabolism of BD at least at high concentrations. Both DMDTC and its diethyl analog (DEDTC) bind with CYP 2E1 and CYP 2A6. Both of these isoforms are important in the initial oxidative metabolism of butadiene and other olefins. In co-exposure studies in mice of DMDTC with BD or with epoxybutene (EB), we found that there was a reduced increase in genotoxic activity based on micronuclei induction compared with BD or EB exposure alone. Treatment with DMDTC significantly increased the protein carbonyl contents of hepatic microsomes compared with that of controls, a finding that may be related to DMDTC's activity as a prooxidant. Co-exposure with DMDTC and EB increased hepatic microsomal carbonyls to levels significantly greater than those of DMDTC-treated mice, while EB administration in the absence of DMDTC did not change protein carbonyls relative to those of controls. The increase in hepatic microsomal protein carbonyls suggests that DMDTC may modulate EB metabolism towards the formation of reactive intermediates that react with proteins. The present molecular modeling and mechanistic studies suggest that co-exposure of BD and DMDTC is a plausible biological hypothesis regarding increased leukemia risk among SBR workers.
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PMID:Application of process chemistry and SAR modelling to the evaluation of health findings of lower olefins. 1139 13

Deutero-substituted (alpha,alpha,alpha',alpha'-tetradeuterated) derivatives of ifosfamide (IF-d(4)) and its bromo analogue were synthesised. In vitro metabolic studies showed that microsomal hydroxylation of IF-d(4) is slower than for unlabelled compound, suggesting that kinetic isotope effect operates during those transformations. At the same time deutero-substituted derivatives are more active against L1210 leukaemia in mice than unlabelled compounds, suggesting a negative role of side-chain hydroxylation metabolic pathways in the anticancer activity of ifosfamide and its analogues.
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PMID:Studies on the side-chain hydroxylation of ifosfamide and its bromo analogue. 1181 13


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