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)

Fluorescence in situ hybridization (FISH) is becoming increasingly used to detect chromosomal changes in cancer cytogenetics. Here, we report its use in human HL60 cells to detect aneuploidy induced by the benzene metabolite, 1,2,4-benzenetriol (BT). Human centromeric probes specific for chromosomes 9 and 7 were used. Untreated HL60 cells were 0.72 +/- 0.29% hyperdiploid for chromosome 9. Treatment with 5 microM BT increased this level 3-fold to 2.20 +/- 0.87% and 50 microM increased it 4-fold to 2.96 +/- 0.74%. Similar results were obtained with the chromosome 7 probe. The induction of aneuploidy by BT is therefore not chromosome-specific nor is it artifactual. Immunocytochemical staining with anti-tubulin antibodies also showed that BT disrupted microtubule organization at these concentrations. Thus, mitotic spindle disruption probably plays an important role in BT-induced aneuploidy. Trisomy and not tetrasomy accounted for the majority of the hyperdiploidy induced by BT in the two C-group chromosomes 7 and 9. Since trisomy of C-group chromosomes is commonly observed in leukemia, BT-induced aneuploidy may be involved in benzene-induced leukemia.
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PMID:Detection of 1,2,4-benzenetriol induced aneuploidy and microtubule disruption by fluorescence in situ hybridization and immunocytochemistry. 750 57

The myelotoxicity, including leukemia, associated with benzene exposure has been attributed to the further activation of benzene-derived metabolites. In a previous study, we observed that (Cu(II) strongly mediates the oxidation of hydroquinone (HQ) producing benzoquinone (BQ) and H2O2 through Cu(II)/Cu(I) redox mechanism. Since copper exists in the nucleus and is closely associated with chromosomes and DNA, in this study we investigated whether this chemical--metal redox system induces strand breaks in phi X-174 RFI plasmid DNA. In the presence of micromolar concentrations of Cu(II) and HQ, both single and double strand breaks were induced, whereas HQ, Cu(II), H2O2 or BQ alone at the employed concentrations elicited no significant damage to DNA. The HQ/Cu(II) system was at least twice as efficient as a H2O2/Cu(II) system at inducing DNA strand breaks. Of Cu(II), Fe(III), Mn(II), Cd(II) and Zn(II), only HQ/Cu(II) induced extensive DNA strand breaks. Among HQ, 1,2,4-benzenetriol (BT), catechol and phenol, HQ/Cu(II) and BT/Cu(II) were the two most efficient DNA cleaving systems. The presence of bathocuproinedisulfonic acid (BCS) or catalase prevented the HQ/Cu(II)-induced DNA strand breaks. In addition, the HQ/Cu(II)-induced DNA strand breaks could be completely blocked by reduced glutathione and dithiothreitol, but not by L-cysteine. The interaction of L-cysteine with copper in the absence of HQ induced significant DNA strand breaks with the same pattern of DNA strand breaks as that of HQ/Cu(II) plus L-cysteine. In contrast to the HQ/Cu(II) system, a HQ/myeloperoxidase (MPO)/H2O2 system did not induce any DNA strand breaks, and furthermore, the presence of MPO inhibited the HQ/Cu(II)-induced DNA strand breaks. When DNA pretreated with Cu(II) was exposed to HQ, DNA strand breaks were formed that could be prevented by BCS or catalase, indicating that DNA-bound copper can undergo redox cycling in the presence of HQ, generating H2O2. Similar to the H2O2/Cu(II) system, the HQ/Cu(II)-induced DNA strand breaks could not be efficiently inhibited by hydroxyl radical scavengers but could be protected by singlet oxygen scavengers, indicating that the localized generation of singlet oxygen or a singlet oxygen-like entity, possibly a copper-peroxide complex, rather than free hydroxyl radical probably plays a role in the HQ/Cu(II)-induced DNA strand breaks. The above results suggest that macromolecule-associated copper and reactive oxygen generation may be important factors in the mechanism of HQ-induced DNA damage in target cells.
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PMID:DNA damage resulting from the oxidation of hydroquinone by copper: role for a Cu(II)/Cu(I) redox cycle and reactive oxygen generation. 839 44

Benzene, an important industrial chemical, is myelotoxic and leukemogenic in humans. It is metabolized by cytochrome P450 2E1 to various phenolic metabolites which accumulate in the bone marrow. Bone marrow contains high levels of myeloperoxidase which can catalyze the further metabolism of the phenolic metabolites to reactive free radical species. Redox cycling of these free radical species produces active oxygen. This active oxygen may damage cellular DNA (known as oxidative DNA damage) and induce genotoxic effects. Here we report the induction of oxidative DNA damage by benzene and its phenolic metabolites in HL60 cells in vitro and in the bone marrow of C57BL/6 x C3H F1 mice in vivo utilizing 8-hydroxy-2'-deoxyguanosine as a marker. HL60 cells (a human leukemia cell line) contain high levels of myeloperoxidase and were used as an in vitro model system. Exposure of these cells to phenol, hydroquinone, and 1,2,4-benzenetriol resulted in an increased level of oxidative DNA damage. An increase in oxidative DNA damage was also observed in the mouse bone marrow in vivo 1 h after benzene administration. A dose of 200 mg/kg benzene produced a 5-fold increase in the 8-hydroxydeoxyguanosine level. Combinations of phenol, catechol, and hydroquinone also resulted in significant increases in steady state levels of oxidative DNA damage in the mouse bone marrow but were not effective when administered individually. Administration of 1,2,4-benzenetriol alone did, however, result in a significant increase in oxidative DNA damage. This represents the first direct demonstration of active oxygen production by benzene and its phenolic metabolites in vivo. The conversion of benzene to phenolic metabolites and the subsequent production of oxidative DNA damage may therefore play a role in the benzene-induced genotoxicity, myelotoxicity, and leukemia.
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PMID:Benzene and its phenolic metabolites produce oxidative DNA damage in HL60 cells in vitro and in the bone marrow in vivo. 843 49

The triphenolic metabolite of benzene, 1,2,4-benzenetriol (BT), is readily oxidized to its corresponding quinone via a semiquinone radical. During this process, active oxygen species are formed that may damage DNA and other cellular macromolecules. The ability of BT to induce micronuclei (MN) and oxidative DNA damage has been investigated in both human lymphocytes and HL60 cells. An antikinetochore antibody based micronucleus assay was used to distinguish MN containing kinetochores and potentially entire chromosomes (kinetochore-positive, K+) from those containing acentric chromosome fragments (kinetochore-negative, K-). BT increased the frequency of MN formation twofold in lymphocytes and eightfold in HL60 cells with the MN being 62% and 82% K+, respectively. A linear dose-related increase in total MN, mainly in K(+)-MN, was observed in both HL60 cells and lymphocytes. Addition of copper ions (Cu2+) potentiated the effect of BT on MN induction threefold in HL60 cells and altered the pattern of MN formation from predominantly K+ to K-. BT also increased the level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a marker of active oxygen-induced DNA damage. Cu2+ again enhanced this effect. Thus, BT has the potential to cause both numerical and structural chromosomal changes in human cells. Further, it may cause point mutations indirectly by generating oxygen radicals. BT may therefore play an important role in benzene-induced leukemia.
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PMID:Benzene metabolite, 1,2,4-benzenetriol, induces micronuclei and oxidative DNA damage in human lymphocytes and HL60 cells. 849 Dec 13

Benzene is a clastogenic and carcinogenic agent that induces acute myelogenous leukemia in humans and multiple of tumors in animals. Previous research has indicated that benzene must first be metabolized to one or more bioactive species to exert its myelotoxic and genotoxic effects. To better understand the possible role of individual benzene metabolites in the leukemogenic process, as well as to further investigate inhibition of topoisomerase II by benzene metabolites, a series of known and putative benzene metabolites, phenol, 4,4'-biphenol, 2,2'-biphenol, hydroquinone, catechol, 1,2,4-benzenetriol, 1,4-benzoquinone, and trans-trans-muconaldehyde were tested for inhibitory effects in vitro on the human topoisomerase II enzyme. With minor modifications of the standard assay conditions, 1,4-benzoquinone and trans-trans-muconaldehyde were shown to be directly inhibitory, whereas all of the phenolic metabolites were shown to inhibit enzymatic activity following bioactivation using a peroxidase activation system. The majority of compounds tested inhibited topoisomerase II at concentrations at or below 10 microM. These results confirm and expand upon previous findings from our laboratory and indicate that many of the metabolites of benzene could potentially interfere with topoisomerase II. Since other inhibitors of topoisomerase II have been shown to induce leukemia in humans, inhibition of this enzyme by benzene metabolites may also play a role in the carcinogenic effects of benzene.
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PMID:Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites. 911 13

Two of the most common cytogenetic changes in therapy- and chemically-related leukemia are the loss and long (q) arm deletions of chromosomes 5 and 7 (i.e. -5, -7, del(5q) and del(7q)). We have used a novel fluorescence in situ hybridization (FISH) procedure to determine if the benzene metabolites hydroquinone (HQ) and 1,2,4-benzenetriol (BT) can induce these specific changes in human lymphocytes cultured as whole blood. Metaphase spreads were prepared and hybridized with centromeric probes for chromosomes 1, 5 and 7 and sequence specific probes for 5q31 and 7q36-qter. HQ and BT significantly increased monosomy 5 and 7 by 3-5 fold (p < 0.0001). Both HQ and BT also significantly increased the rate of del(5q) and del(7q) by 8-12 fold (p < 0.0001). Chromosome 7 was especially susceptible to aneusomy induction by HQ and BT at low doses. These results show that metabolites of benzene are highly effective in inducing changes in chromosomes 5 and 7 that are involved in the development of myeloid leukemia.
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PMID:Benzene metabolites induce the loss and long arm deletion of chromosomes 5 and 7 in human lymphocytes. 959 66

Benzene is a widespread human carcinogen, inducing leukemia and hematotoxicity. Exposure of human lymphocytes to benzene metabolites has been shown to cause genetic damage, including aneusomy and chromosome aberrations. In order to detect the specific chromosomal changes in chromosomes 5, 7, 8, and 21 induced by benzene metabolites, 1,2,4-benzenetriol (BT), hydroquinone (HQ), and trans,trans-muconic acid (t,t-MA), fluorescence in situ hybridization (FISH) procedure in the metaphase spread of human lymphocytes was employed. Treatment with BT, HQ and tt-MA resulted in the induction of monosomy 5, 7, 8, and 21 in human lymphocytes in a concentration-dependent manner. All of these metabolites also induced trisomy 5, 7, 8, and 21, but no correlation between frequencies of trisomy and concentration was found. Translocations between chromosome 8 and another unidentified chromosome [t(8:?)] and between chromosome 21 and another unidentified chromosome [t(21:?)] were found. However, translocation between chromosome 8 and 21 [t(8:2 1)] was not found. Results indicate that the benzene metabolites BT, HQ and t,t-MA induce chromosome-specific numerical and structural aberrations, and the fluorescence in situ hybridization (FISH) approach may be a useful and powerful technique for detection of aneuploidy.
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PMID:Detection of chromosome-specific aneusomy and translocation by benzene metabolites in human lymphocytes using fluorescence in situ hybridization with DNA probes for chromosomes 5, 7, 8, and 21. 1193 17

The generation, transmission (e.g. power lines, transformers, service wires, and electrical panels), and use (e.g. home appliances, such as electric blankets, shavers, and televisions) of electrical energy is associated with the production of weak electric and magnetic fields (EMF) which oscillate 50 (Europe) or 60 (USA) times per second (power-line frequency), falling in the extremely-low frequency (ELF) region of the electromagnetic spectrum. Epidemiological reports suggest a possible association between exposure to ELF-EMF and an increased risk of cancer (e.g. childhood acute leukaemia). Benzene is an established human leukomogen. This xenobiotic, which is unlikely to be the ultimate carcinogen, is metabolized in the liver to its primary metabolite phenol, which is hydroxylated to hydroquinone (1,4-benzenediol) and 1,2,4-benzenetriol. In this in vitro approach, to test the genotoxic and / or co-genotoxic potency of ELF-EMF, the cytokinesis block micronucleus (MN) method with Jurkat cells has been used. A 50 Hz magnetic field (MF) of 5 mT field strength was applied for different length of time (from 1 to 24 h), either alone or with benzene, 1,4-benzenediol, or 1,2,4-benzenetriol. Our preliminary results show that, after 24 h exposure, the frequency of micronucleated cells in MF-exposed cultures is 1.9 fold higher than in sham-exposed (control) cultures. Benzene exposure does not show any cytogenetic activity, whereas 1,4-benzenediol or 1,2,4-benzenetriol alone significantly affect the number of MN in Jurkat cells, as compared to untreated cultures. Moreover, co-exposure to ELF-MF does not seem to affect the frequency of micronuclei induced by benzene, 1,4-benzenediol, or 1,2,4-benzenetriol.
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PMID:Micronucleus induction in cells co-exposed in vitro to 50 Hz magnetic field and benzene, 1,4-benzenediol (hydroquinone) or 1,2,4-benzenetriol. 1459 48

During the last two decades, concerns have arisen regarding a possible association between extremely-low frequency (ELF) electromagnetic fields (EMF) exposure and cancer incidence (e.g. childhood acute leukaemia, cancer of the nervous system, and lymphomas). In 1979, Wertheimer and Leeper firstly reported an excess of cancer mortality among children living in homes located near power lines and presumably exposed to elevated magnetic fields. Subsequently, a large number of epidemiological studies investigated the possible association between residential or occupational exposure to ELF-EMF and cancer. Several in vivo and in vitro models have been investigated with the effort to determine a link, if any, between such fields and mutagenesis and to determine the possible mechanism of cancer risk. However, a causal relationship between exposure to ELF-EMF and cancer has been suggested but has not been unequivocally demonstrated. In 1998, following an analysis of the results retrieved in the literature, the U.S. National Institute of Environmental Health Sciences proposed to apply a "possible human carcinogen" category (Group 2B) to ELF-EMF. More recently, in 2002, the same classification for ELF-MF was proposed by the International Agency for Research on Cancer. In this in vitro approach, to test the genotoxic and/or co-genotoxic potency of ELF-MF, we used the alkaline single-cell microgel-electrophoresis (comet) assay and the cytokinesis block micronucleus test. Co-exposure assays were performed in the presence of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4-nitroquinoline N-oxide (4NQO), benzene, 1,4-benzenediol (1,4-BD), or 1,2,4-benzenetriol (1,2,4-BT). An ELF-MF (50 Hz, 5 mT) was obtained by a system composed of capsulated induction coils. ELF-MF alone was unable to cause direct primary DNA damage. Whereas, an increased extent of DNA damage was observed in cells co-exposed to ELF-MF and MNNG, 1,4-BD, or 1,2,4-BT. An opposite trend was observed in cells treated with 4NQO and co-exposed to ELF-MF. Moreover, the frequency of micronucleated cells in ELF-MF-exposed cells was higher than in control cultures. Our findings suggest that the tested ELF-MF (50 Hz, 5 mT) possess genotoxic (micronucleus test) and co-genotoxic (comet assay) capabilities. The possibility that ELF-MF might interfere with the genotoxic activity of xenobiotics has important implications, since human populations are likely to be exposed to a variety of genotoxic agents concomitantly with exposure to this type of physical agent.
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PMID:[Evaluation of genotoxic and/or co-genotoxic effects in cells exposed in vitro to extremely-low frequency electromagnetic fields]. 1555 38

Although benzene induces leukemias in humans, the compound is not believed to generate chromosomal damage directly. Rather, benzene is thought to act through a series of phenolic- and quinone-based metabolites, especially 1,4-benzoquinone. A recent study found that 1,4-benzoquinone is a potent topoisomerase II poison in vitro and in cultured human cells [Lindsey et al. (2004) Biochemistry 43, 7363-7374]. Because benzene is metabolized to multiple compounds in addition to 1,4-benzoquinone, we determined the effects of several phenolic metabolites, including catechol, 1,2,4-benzenetriol, 1,4-hydroquinone, 2,2'-biphenol, and 4,4'-biphenol, on the DNA cleavage activity of human topoisomerase II alpha. Only 1,4-hydroquinone generated substantial levels of topoisomerase II-mediated DNA scission. DNA cleavage with this compound approached levels observed with 1,4-benzoquinone (approximately 5- vs 8-fold) but required a considerably higher concentration (approximately 250 vs 25 microM). 1,4-Hydroquinone is a precursor to 1,4-benzoquinone in the body and can be activated to the quinone by redox cycling. It is not known whether the effects of 1,4-hydroquinone on human topoisomerase II alpha reflect a lower reactivity of the hydroquinone or a low level of activation to the quinone. The high concentration of 1,4-hydroquinone required to increase enzyme-mediated DNA cleavage is consistent with either explanation. 1,4-Hydroquinone displayed attributes against topoisomerase II alpha, including DNA cleavage specificity, that were similar to those of 1,4-benzoquinone. However, 1,4-hydroquinone consistently inhibited DNA ligation to a greater extent than 1,4-benzoquinone. This latter result implies that the hydroquinone may display (at least in part) independent activity against topoisomerase II alpha. The present findings are consistent with the hypothesis that topoisomerase II alpha plays a role in the initiation of specific types of leukemia that are induced by benzene and its metabolites.
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PMID:Effects of benzene metabolites on DNA cleavage mediated by human topoisomerase II alpha: 1,4-hydroquinone is a topoisomerase II poison. 1583 37


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