Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 is a potent hematotoxin and has been shown to cause leukemia in man. Chronic toxicity studies indicate that B6C3F1 mice are more susceptible than F334/N rats to benzene toxicity. The purpose of the studies presented in this paper was to determine if there were metabolic differences between F344/N rats and B6C3F1 mice which might be responsible for this increased susceptibility. Metabolites of benzene in blood, liver, lung, and bone marrow were measured during and following a 6-hr 50 ppm exposure to benzene vapor. Hydroquinone glucuronide, hydroquinone, and muconic acid, which reflect pathways leading to potential toxic metabolites of benzene, were present in much greater concentrations in the mouse than in rat tissues. Phenylsulfate, a detoxified metabolite, and an unknown water-soluble metabolite were present in approximately equal concentrations in these two species. These results indicate that the proportion of benzene metabolized via pathways leading to the formation of potentially toxic metabolites as opposed to detoxification pathways was much higher in B6C3F1 mice than in F344 rats, which may explain the higher susceptibility of mice to benzene-induced hematotoxicity and carcinogenicity.
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PMID:Differences in the metabolism and disposition of inhaled [3H]benzene by F344/N rats and B6C3F1 mice. 337 10

New antitumor antibiotics, macbecins I and II, were isolated from the culture broth of Nocardia sp. No. C-14919. Macbecins I and II belong to the ansamycin group and have a benzoquinone and hydroquinone nucleus, respectively. Both showed antitumor activity against murine leukemia P 388 in vivo.
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PMID:Macbecins I and II, new antitumor antibiotics. II. Isolation and characterization. 738 Jul 30

Increased frequencies of structural and numerical chromosomal aberrations have been observed in the lymphocytes of benzene-exposed workers. Similar aberrations occurring in bone-marrow cells may contribute to the increased incidence of leukemia seen in these populations. Fluorescence in situ hybridization with chromosome-specific DNA probes is a relatively new technique which shows promise for the identification of aneuploidy-inducing agents. In these studies, fluorescence in situ hybridization with several chromosome-specific DNA probes was used to investigate the ability of the benzene metabolite hydroquinone to induce hyperdiploidy in interphase human lymphocytes. Using a classical satellite probe specific for human chromosome 9, a significant dose-related increase in the frequency of cells containing 3 or more hybridization regions was observed following the in vitro exposure of lymphocytes to hydroquinone at concentrations from 75 to 150 microM. At the 100-microM concentration of hydroquinone, the frequency of nuclei containing 3 or more hybridization regions was determined using probes for chromosomes 1, 7 and 9. Significantly higher frequencies of affected nuclei were observed using the chromosome 1 and 9 probes when compared to the chromosome 7 probe. To establish whether this difference was due to the nonrandom involvement of these chromosomes in hydroquinone-induced hyperdiploidy or to chromosomal breakage within the chromosomal region targeted by these probes, a multicolor fluorescence in situ hybridization approach was developed using probes to two adjacent regions on chromosome 1. Using this tandem-labeling approach, the frequency of nuclei with multiple hybridization regions and the origin of the regions was determined by scoring slides labeled simultaneously with the chromosome 7 alpha satellite probe and the adjacent alpha and classical satellite probes for chromosome 1. The results of these studies confirmed that hydroquinone exposure resulted in a significant increase in hyperdiploid nuclei, but indicated that the different frequency of nuclei containing 3 or more hybridization regions observed using the chromosome 1 and 7 probes, was due to breakage within the chromosomal region targeted by the chromosome 1 classical satellite probe. These results indicate that hydroquinone may contribute significantly to the numerical and structural aberrations observed in benzene-exposed workers. In addition, the multicolor fluorescence in situ hybridization approach utilized in these studies promises to be a powerful technique for the detection of chromosomal breakage occurring in interphase human cells.
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PMID:Detection of hyperdiploidy and chromosome breakage in interphase human lymphocytes following exposure to the benzene metabolite hydroquinone using multicolor fluorescence in situ hybridization with DNA probes. 751 7

Toxiusol, a natural product isolated from the Red Sea sponge Toxiclona toxius, has been shown to be a potent inhibitor of various viral reverse transcriptases (RT) [i.e., of human immunodeficiency virus (HIV-1), equine infectious anemia virus, and murine leukemia virus] and cellular DNA polymerases (i.e., of DNA polymerases alpha and beta and Escherichia coli DNA polymerase I). A thorough investigation of the mode of inhibition was conducted with HIV-1 RT-associated DNA polymerase activity. The inhibition is unaffected by the nature of template-primer used. The inhibitory active site of toxiusol is attributable to the polar moieties at the benzene ring. The presence of either sulfate groups in the natural lead compound or hydroxyl groups in the corresponding hydroquinone is critical, because both compounds are equally effective at low micromolar concentrations. Conversely, the presence of acetyl groups in the same position in the derivative toxiusol diacetate lowers significantly or abolishes the inhibitory activity. Toxiusol binds the HIV-1 RT irreversibly and in a noncompetitive way with high affinity (Ki = 1.2 microM), probably through polar groups. The replacement with acetyl moieties in the analog toxiusol diacetate hampers the binding of the inhibitor to the enzyme (Ki increases to about 26 microM). Still, the compound binds irreversibly, probably through its hydrophobic structure skeleton. Toxiusol diacetate loses its ability to inhibit the first step in the DNA polymerization process (that is, the formation of the DNA-enzyme complex as measured by a gel retardation assay), which contributes to its poor inhibitory capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of inhibition of HIV reverse transcriptase by toxiusol, a novel general inhibitor of retroviral and cellular DNA polymerases. 753 6

Benzene is a human carcinogen; exposure to benzene can result in aplastic anemia and leukemia. Data from animal models are frequently used in the risk assessment for benzene. In rodent studies, mice have been shown to be more sensitive to benzene-induced hematotoxicity than rats. In this regard, we have observed that bone marrow stromal cells from mice were significantly more susceptible to the cytotoxicity induced by the benzene metabolites hydroquinone (HQ) and benzoquinone (BQ) than cells from rats. Since cellular glutathione (GSH) and quinone reductase (QR) are known to play critical roles in modulating HQ-induced cytotoxicity, we have measured the GSH content and the QR and glutathione S-transferase (GST) activity in stromal cells from both species. In rat cells, the GSH content and the QR specific activity were 2 and 28 times as much as those from mice, respectively. GSH and QR in both mouse and rat stromal cells were inducible by 1,2-dithiole-3-thione (D3T). D3T pretreatment of both mouse and rat stromal cells resulted in a marked protection against HQ-induced toxicity. Pretreatment of both mouse and rat stromal cells with GSH ethyl ester also provided a dramatic protection against HQ-induced toxicity. Conversely, dicoumarol, an inhibitor of QR, enhanced the HQ-induced toxicity in stromal cells from both mice and rats, indicating an important role for QR in modulating HQ-induced stromal toxicity in both species. Buthionine sulfoximine (BSO), which depleted GSH significantly in both species, potentiated the HQ-induced toxicity in mouse but not in rat stromal cells. Surprisingly, incubation of stromal cells with BSO resulted in a significant induction of QR, especially in rats. The failure of BSO to potentiate HQ-induced toxicity in rat stromal cells may be due to the concomitant induction of QR by BSO. Overall, this study demonstrates that the differences in stromal cellular GSH content and QR activity between mice and rats contribute to their respective susceptibility to HQ-induced cytotoxicity in vitro, and may be involved in the greater in vivo sensitivity of mice to benzene-induced hematotoxicity.
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PMID:Differences in xenobiotic detoxifying activities between bone marrow stromal cells from mice and rats: implications for benzene-induced hematotoxicity. 756 17

Mortality in a 1942-1990 cohort of 858 men and 21 women employed in the manufacture and use of hydroquinone was evaluated through 1991. Average exposure concentrations, 1949-1990, ranged from 0.1 to 6.0 mg/m3 for hydroquinone dust and from less than 0.1 to 0.3 for quinone vapor (estimated 8-h time-weighted averages). Compared with general population and occupational referents, there were statistically significant deficits in total mortality and deaths due to cancer. No significant excesses were observed for such hypothesized causes as kidney cancer [2 observed vs 1.3 expected (both control groups), P approximately 0.39], liver cancer (0 vs 0.8, 1.3), and leukemia (0 vs 2.3, 2.7). Dose-response analyses of selected causes of death, including renal carcinoma, demonstrated no statistically significant heterogeneities or linear trends according to estimated career hydroquinone exposure (mg/m3-years) or time from first exposure.
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PMID:Mortality study of employees engaged in the manufacture and use of hydroquinone. 759 Nov 88

Benzene exposure causes leukemia and lymphomas. Recent epidemiological findings have also shown an association between cigarette smoking and an increased risk of leukemia. However, further evidence is required to document the biological plausibility of this association. In evaluating this link, it is important to note that cigarette smoke contains benzene and various pyrolytic compounds, among other carcinogens. This study aims to determine the uptake of benzene by measuring 3 benzene-related compounds in cigarette smokers and non-smokers. Urinary concentrations of catechol (CAT), hydroquinone (HQ), and trans,trans-muconic acid (tt-MA) were measured by high-performance liquid chromatography (HPLC) with fluorimetric and UV detection, respectively. The results showed that these compounds were present in all urine samples. However, the concentrations were significantly higher in smokers than in non-smokers. The mean level of urinary tt-MA was 0.19 +/- 0.09 mg/g creatinine for 46 male smokers and the corresponding value for 40 non-smokers was 0.14 +/- 0.07 mg/g creatinine. The mean concentrations of HQ and CAT were 0.81 +/- 0.4 and 3.51 +/- 2.6 mg/g creatinine for smokers, and 0.45 +/- 0.4 and 1.94 +/- 1.2 mg/g creatinine for non-smokers, respectively. These results suggest that cigarette smoking is associated with a significant additional exposure to benzene and its related compounds. Furthermore, significant correlations were observed between the concentrations of cotinine, the metabolite of nicotine, and the above compounds. These findings suggest that the exposure originated from cigarette smoking.
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PMID:Elevated levels of benzene-related compounds in the urine of cigarette smokers. 792 15

Metabolism of benzene results in the formation of multiple metabolites, including hydroquinone (HQ). HQ is a reducing co-substrate for peroxidase enzymes, and the resultant semiquinone and para-benzoquinone (p-BQ) may bind to DNA. The role of peroxidase activation in the formation of DNA adducts by benzene metabolites has not been established. In this study we investigated the role of peroxidase activation in the formation of DNA adducts by HQ and p-BQ in HL-60 cells, human bone marrow (HBM) cells, mouse bone marrow macrophages (MBMM) and the U-937 and Raji leukemia cell lines. Adduct formation was measured by P1-enhanced 32P-postlabeling; peroxidase activity was measured with a spectrophotometric assay. Treatment with p-BQ resulted in the formation of two DNA adducts in all of the cell lines. The DNA adducts were identical in all of the cells, however, the adduct level varied by 80-fold. Treatment with HQ produced one DNA adduct in HL-60 cells, HBM and MBMM; no adducts were detected in U-937 or Raji cells. The HQ-DNA adducts in the three cell lines were identical. The adduct level was highest in the HL-60 cells, followed by HBM and MBMM. There was a statistically significant correlation between peroxidase activity and the formation of HQ-DNA adducts. These results suggest that peroxidase-mediated metabolism is involved in the activation of HQ to form DNA adducts in mouse bone marrow and HBM.
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PMID:Peroxidase activation of hydroquinone results in the formation of DNA adducts in HL-60 cells, mouse bone marrow macrophages and human bone marrow. 824 63

Benzene, an important industrial solvent and constituent of unleaded gasoline, causes leukemia and aplastic anemia in humans. Mice are more sensitive than rats to benzene toxicity, though neither species has been shown to respond consistently with benzene-induced leukemia. Benzene biotransformation in liver to phenol, hydroquinone, catechol and/or muconaldehyde is thought to be necessary for its hematotoxicity and/or genotoxicity. Our goal is to develop a mathematical simulation model capable of describing the pathways and kinetics of benzene metabolism by rat and mouse liver microsomes and to assess the role of species metabolic differences in species sensitivity. Microsomes were incubated with 4 microM [U-14C]-benzene or 4 microM [U-14C]phenol. Metabolite production was quantified by extraction into ethyl acetate, HPLC separation and liquid scintillation spectroscopy. After 45 min, mouse liver microsomes converted 20% of the benzene to phenol, 31% to hydroquinone and 2% to catechol. Rat liver microsomes converted 23% of benzene to phenol, 8% to hydroquinone and 0.5% to catechol. Production of hydroquinone and catechol continued for 90 min for mouse liver microsomes, while production by rat liver microsomes had virtually ceased by 90 min. Muconic acid production by mouse liver microsomes was < 0.2% and < 0.04% from benzene and phenol respectively after 90 min. A quantitative simulation model was constructed to describe the in vitro metabolism of benzene, incorporating the reaction sequences: benzene-->phenol-->catechol-->trihydroxybenzene and phenol-->hydroquinone-->trihydroxybenzene. In the model, all of the reaction steps are assumed to be catalyzed by the same enzyme(s), cytochrome(s) P450, and benzene, phenol, hydroquinone and catechol in solution are all assumed to compete, through reversible binding, for the same reaction site(s) on cytochrome(s) P450. The simulation model accurately described both the benzene and phenol kinetic data, supporting this proposed mechanism. In particular, this model suggests that the observed inhibition of benzene on phenol metabolism, and of phenol on benzene metabolism, occurs through competition for a common reaction site, which can also bind catechol and hydroquinone.
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PMID:Benzene and phenol metabolism by mouse and rat liver microsomes. 826 15

The synthesis and cytotoxic properties of benzimidazole-based DNA-cleaving agents are presented herein. These agents include pyrrolo[1,2-a]benzimidazole (PBI), benzimidazole (BI), and tetrahydropyrido[1,2-a]benzimidazole (TPBI) analogues. As a result of these studies, it is concluded that the pyrrolo ring is not necessary for cytotoxicity (PBI is only slightly more cytotoxic than BI) but that homologation of the pyrrolo ring by one carbon results in a system, TPBI, prone to decomposition. Another conclusion is that the 6-aziridinyl derivative of the PBI system is more potent than the 7-aziridinyl derivative. Comparative studies with known antitumor agents revealed that the benzimidazole-based DNA-cleaving agents possess a unique spectrum of activity. Noteworthy observations are the high level of cytotoxicity against melanoma cell lines and the complete absence of activity against leukemia cell lines. The reductive activation and DNA-cleavage properties of the most active analogue (BI-A) are also presented. Reduction of the quinone ring to the hydroquinone results in nucleophile and proton trapping by the aziridinyl group. Documented nucleophiles include water and the oxygen anion of 5'-dAMP. In addition, reduced BI-A reacts with DNA to form a stable adduct, which cleaves at G+A bases upon heating in basic gel-loading solution.
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PMID:Structure-activity studies of benzimidazole-based DNA-cleaving agents. Comparison of benzimidazole, pyrrolobenzimidazole, and tetrahydropyridobenzimidazole analogues. 828 4


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