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)

Albumin adducts of benzene oxide (BO-Alb) and 1,4-benzoquinone (1,4-BQ-Alb) were investigated among 134 workers exposed to benzene and 51 unexposed controls in Tianjin, China. Concentrations of both adducts increased with benzene exposure [range = 0.07-46.6 parts/million (ppm); median = 3.55 ppm] and with urinary cotinine. Adduct levels were less than proportional to benzene exposure, suggesting saturable CYP 2E1 metabolism of benzene. Because the transition from linear to saturable metabolism began at approximately 1 ppm, the common assumption of linear kinetics at much higher benzene exposures could lead to substantial underestimation of leukemia risks. Adduct levels were generally lower in older workers, indicating that CYP 2E1 metabolism diminished with age, at approximately 2%/year of life. The ratio of 1,4-BQ-Alb:BO-Alb decreased with age and coexposure to toluene, and increased with alcohol consumption. This indicates that factors affecting CYP 2E1 metabolism exerted a greater role on production of 1,4-BQ than BO, presumably because of the second oxidation step from phenol to hydroquinone. The adduct ratio was also positively associated with urinary cotinine, suggesting that both benzene and hydroquinone from cigarette smoke affected adduct levels. Results of a limited time course study of 11 subjects indicated moderate chemical instability of 1,4-BQ-Alb (half life = 13.5 days compared with 21 days for normal Alb turnover), whereas no evidence of instability of BO-Alb was observed. This study illustrates that Alb adducts can be used to investigate the dispositions of reactive metabolites of procarcinogens in humans, provided that exposures are adequately characterized in the month preceding blood collection.
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PMID:Albumin adducts of benzene oxide and 1,4-benzoquinone as measures of human benzene metabolism. 1188 1

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

Benzene can induce hematotoxicity and leukemia in humans and mice. Since a review of the literature shows that the CYP2E1 knockout mouse is not known to possess any benzene toxicity, the metabolism of benzene by CYP2E1 in the liver is regarded to be prerequisite for its cytotoxicity and genotoxicity, although the mechanism is not fully understood yet. Because it was found some years ago that benzene was also a substrate for CYP1A1, we investigated the involvement of the aryl hydrocarbon receptor (AhR) in benzene hematotoxicity using AhR wild-type (AhR(+/+)), heterozygous (AhR(+/-)), and homozygous (AhR(-/-)) male mice. Interestingly, following a 2-week inhalation of 300 ppm benzene (a potent dose for leukemogenicity), no hematotoxicity was induced in AhR(-/-) mice. Further, there were no changes in cellularity of peripheral blood and bone marrow (BM), nor in levels of granulocyte-macrophage colony-forming units in BM. This lack of hematotoxicity was associated with the lack of p21 overexpression, which was regularly seen in the wild-type mice following benzene inhalation. Combined treatment with two major benzene metabolites, phenol and hydroquinone, induced hemopoietic toxicity, although it was not known whether this happened due to a surprising lack of expression of CYP2E1 by AhR knockout, or due to a lack of other AhR-mediated CYP enzymes, including 1A1 (i.e., a possible alternative pathway of benzene metabolism). The former possibility, evaluated in the present study, failed to show a significant relationship between AhR and the expression of CYP2E1. Furthermore, a subsequent evaluation of AhR expression after benzene inhalation tended to show higher but less significant expression in the liver, and none in the BM, compared with sham control. Although this study failed to identify the more likely of the above-mentioned two possibilities, the study using AhR knockout mice on benzene inhalation presents the unique possibility that the benzene toxicity may be regulated by AhR signaling.
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PMID:Aryl hydrocarbon receptor mediates benzene-induced hematotoxicity. 1238 43

Hydroquinone is used an antioxidant in the rubber industry and as a developing agent in photography. It is also an intermediate in the manufacture of rubber and food antioxidants and monomer inhibitors. Hydroquinone and products containing hydroquinone are used as depigmenting agents to lighten skin. NTP Toxicology and Carcinogenesis studies were conducted by administering hydroquinone (greater than 99% pure) in corn oil or water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Additionally, genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Preliminary 3-day dermal studies were conducted with rats and mice using sufficient hydroquinone in 95% ethanol to crystallize on the skin (4 or 40 mg per animal); conjugated metabolites of hydroquinone were detected in the urine. Fourteen-day dermal studies were conducted at doses up to 3,840 mg/kg for rats and 4,800 mg/kg for mice. No toxic effects were seen in the 3- or 14-day dermal studies. Therefore, in further evaluations of hydroquinone, the gavage route of administration was used. Results of Fourteen-Day and Thirteen-Week Studies: Fourteen-day gavage studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1,000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg. All rats receiving 1,000 mg/kg and 1/5 male and 4/5 female rats receiving 500 mg/kg died before the end of the 14 days. Compound-related clinical signs in rats included tremors lasting up to 30 minutes after each dosing at 500 and 1,000 mg/kg. In the 14-day gavage studies with mice, 4/5 male mice and 5/5 female mice receiving 500 mg/kg and 3/5 males receiving 250 mg/kg died before the end of the studies. Tremors followed by convulsions were seen at 250 and 500 mg/kg. In the 13-week studies, doses for rats and mice ranged from 25 to 400 mg/kg. All rats receiving 400 mg/kg and 3/10 female rats receiving 200 mg/kg died before the end of the studies. The mean body weight at necropsy of male rats administered 100 or 200 mg/kg was about 8%-9% lower than that of vehicle controls. Mean body weights of vehicle control and dosed female rats at necropsy were similar. Tremors and convulsions were observed after dosing in most rats receiving 400 mg/kg and in several female rats receiving 200 mg/kg. Inflammation and/or epithelial hyperplasia (acanthosis) of the forestomach were seen in 4/10 male rats and 1/10 female rats receiving 200 mg/kg. Toxic nephropathy, characterized by tubular cell degeneration in the renal cortex, was seen in 7/10 male and 6/10 female rats receiving 200 mg/kg and in 1/10 females receiving 100 mg/kg. In the 13-week studies in mice, 8/10 males and 8/10 females receiving 400 mg/kg and 2/10 male mice receiving 200 mg/kg died early. Mean body weights of dosed and vehicle control mice at necropsy were similar. Liver weight to body weight ratios for dosed male mice were significantly greater than for vehicle controls. Ulceration, inflammation, or epithelial hyperplasia of the forestomach was found in 3/10 male and 2/10 female mice receiving 400 mg/kg and 1/10 females receiving 200 mg/kg. Based on these collective results, 2-year studies were conducted by administering 0, 25, or 50 mg/kg hydroquinone in deionized water by gavage to groups of 65 rats of each sex, 5 days per week. Groups of 65 mice of each sex were administered 0, 50, or 100 mg/kg on the same schedule. Ten rats and 10 mice from each group were killed after 15 months for an interim evaluation. Observations at Fifteen Months: In the rats killed at 15 months, the relative kidney weight for high dose male rats was greater than that for vehicle controls. The hematocrit value, hemoglobin concentration, and erythrocyte count for high dose female rats were decreased. Compound-related increased severity of nephropathy was observed in male rats. In mice killed at 15 months, the relative liver weights for high dose male and female mice were signif and female mice were significantly greater than those for vehicle controls. Lesions seen in the liver of male mice included increased syncytial cells and diffuse cytomegaly. Body Weights, Organ Weights, and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 5%-13% lower than those of vehicle controls after week 73, and those of low dose male rats were 5%-9% lower than those of vehicle controls after week 89. Mean body weights of dosed female rats were similar to those of vehicle controls throughout the study. The relative kidney and liver weights for high dose male rats were higher than those for vehicle controls. Mean body weights of high dose male mice were 5%-8% lower than those of vehicle controls after week 93, and those of high dose female mice were 5%-14% lower after week 20. Relative liver weights were increased for dosed male and high dose female mice. No significant differences in survival were observed between any groups of rats or mice of either sex after 2 years (male rats: vehicle control, 27/55; low dose, 18/55; high dose, 18/55; female rats: 40/55; 27/55; 32/55; male mice: 33/55; 37/54; 36/55; female mice: 37/55; 39/55; 36/55). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nearly all male rats and most female rats in all vehicle control and dosed groups had nephropathy. The severity of this disease was judged to be greater in high dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts, changes observed with advanced renal disease, were increased in male rats. Renal tubular hyperplasia was seen in 2 high dose male rats, and renal tubular adenomas were seen in 4/55 low dose and 8/55 high dose male rats; none was seen in vehicle controls. Mononuclear cell leukemia in female rats occurred with a positive trend, and the incidences in the dosed groups were greater than that in the vehicle controls (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). The historical incidence of leukemia in water gavage vehicle control female F344/N rats is 25% ± 15% and in untreated controls is 19% ± 7%. Compound-related lesions observed in the liver of high dose male mice included anisokaryosis (0/55; 2/54; 12/55), syncytial alteration (5/55; 3/54; 25/55), and basophilic foci (2/55; 5/54; 11/55). The incidences of hepatocellular adenomas were increased in dosed male mice (9/55; 21/54; 20/55), but these increases were offset by decreases in the incidences of hepatocellular carcinomas (13/55; 11/54; 7/55). The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice (male: 5/55; 15/53; 19/54; female: 13/55; 47/55; 45/55). Follicular cell adenomas were seen in 2/55 vehicle control, 1/53 low dose, and 2/54 high dose male mice and in 3/55 vehicle control, 5/55 low dose, and 6/55 high dose female mice, a follicular cell carcinoma was seen in a seventh high dose female mouse. The highest observed incidence of follicular cell adenomas or carcinomas(combined) in historical water gavage vehicle control female B6C3F1 mice is 3/48 (6%). Genetic Toxicology: Hydroquinone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It induced trifluorothymidine (Tft) resistance in mouse L5178Y/TK lymphoma cells in the presence or absence of metabolic activation. An equivocal response was obtained in tests for induction of sex-linked recessive lethal mutations in Drosophila administered hydroquinone by feeding. Hydroquinone induced sister chromatid exchanges (SCEs) in CHO cells both with or without exogenous metabolic activation and caused chromosomal aberrations in the presence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of hydroquinone for male F344/N rats, as shown by marked increases in tubular cell adenomas of the kidney. There was some evidence of carcinogenic activity of hydroquinone for female F344/N rats, as shown by increases in mononuclear cell leukemia. There was no evidence of carcinogenic activity of hydroquinone for male B6C3F1 mice administered 50 or 100 mg/kg in water by gavage. There was some evidence of carcinogenic activity of hydroquinone for female B6C3F1 mice, as shown by increases in hepatocellular neoplasms, mainly adenomas. Administration of hydroquinone was associated with thyroid follicular cell hyperplasia in both male and female mice and anisokaryosis, multinucleated hepatocytes, and basophilic foci of the liver in male mice. Synonyms: 1,4-benzenediol; p-benzenediol; benzohydroquinone; benzoquinol; 1,4-dihydroxybenzene; p-dihydroxybenzene; p-dioxobenzene; p-dioxybenzene; hydroquinol; hydroquinole; a-hydroquinone; p-hydroquinone; p-hydroxyphenol; quinol; b-quinol
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PMID:NTP Toxicology and Carcinogenesis Studies of Hydroquinone (CAS No. 123-31-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 38

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

Human leukemogens, including alkylating chemotherapeutic agents and benzene, enhance granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent proliferation of human CD34+ bone marrow (BM) cells. The extracellular signal-regulated kinase (ERK) pathway plays an important role in GM-CSF-dependent proliferation and also has been implicated in the pathogenesis of acute myelogenous leukemia. Therefore, we investigated the effects of the benzene metabolite, hydroquinone (HQ), on alterations in the GM-CSF signaling pathway in TF-1 erythroleukemia cells and human CD34+ BM cells. HQ treatment in TF-1 cells results in a strong proliferative response that is dependent on ERK activation and GM-CSF production. HQ also induces ERK-dependent AP-1 activation with concomitant increased transcriptional activity of AP-1 reporter gene. However, the kinetics of ERK activation are different between rhGM-CSF and HQ in TF-1 cells: rhGM-CSF results in immediate activation of ERK, whereas HQ activation of ERK is delayed. Further, HQ and rhGM-CSF together produce an immediate increase in ERK phosphorylation, which is sustained for over 48 h. HQ also stimulates colony formation, AP-1 DNA binding and GM-CSF production in human CD34+ BM cells. These results suggest that HQ stimulates proliferation via activation of ERK/AP-1 and is at least partially mediated via the production of GM-CSF.
Leukemia 2004 Jul
PMID:Hydroquinone modulates the GM-CSF signaling pathway in TF-1 cells. 1512 24

The use of hydroquinone as a cosmetic skin-bleaching agent has been forbidden since January 2001. It is now available only on prescription. The ban has been introduced because of medium-term effects such as white patches on the skin, particularly on the face (leukoderma with confetti-like depigmentation), and subcutaneous dark collections of pigment (exogenous ochonosis). Long-term effects are a possibility; cancer being the most likely. Renal adenomas and leukaemia occurred in animal experiments indicating the nephrotoxicity and carcinogenic properties of the substance. It is now known how hydroquinone and its metabolites can cause damage to DNA and inhibit apoptosis of mutated cells. The carcinogenic action of benzene is difficult to attribute to its hydroquinone metabolite. Daily use of hydroquinone causes it to accumulate in the body as absorption into the skin is faster than excretion in the urine. The use of hydroquinone as a skin-bleaching agent is accordingly unsafe and should be completely banned. Alternatives such as azaleic acid and thioctic acid (alpha-lipoic acid) are available.
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PMID:[Toxicological aspects and health risks associated with hydroquinone in skin bleaching formula]. 1512 64

Benzene toxicity is considered to be elicited by its metabolites and phenolic metabolites of benzene are known to induce apoptosis in leukemia cells in culture and in human bone marrow progenitor cells. One potential mechanism of apoptosis induced by benzene metabolites that has not been examined is the production of pro-apoptotic cytokines such as endothelial IL-8 from endothelial cells in bone marrow stroma. In this study, we utilized HL-60 cells which are known to produce the endothelial form of IL-8 (eIL-8) and human bone marrow endothelial cells (HBMEC) as model systems. Hydroquinone (HQ), Catechol (Cat) and benzenetriol (BT) all induced eIL-8 production and apoptosis in HL-60 cells. HQ induced a marked 50-70 fold stimulation of eIL-8 levels and HL-60 cells were shown to have the eIL-8 receptor, CXCR1 thus enabling an autocrine pathway of apoptosis. However, treatment with recombinant eIL-8 failed to induce apoptosis in HL-60 cells as previously reported and antibodies to either IL-8 or CXCR1 did not significantly abrogate benzene metabolite-induced apoptosis. HQ and Cat but not BT also induced stimulation of eIL-8 production in HBMEC. These data demonstrate that although metabolites of benzene induce marked stimulation of eIL-8, this is unlikely to be responsible for apoptosis induced in HL-60 cells. Our data also demonstrates that phenolic metabolites of benzene stimulate the production of eIL-8 from HBMEC suggesting that higher levels of endothelial-derived cytokines may occur in bone marrow after benzene exposure.
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PMID:Stimulation of endothelial IL-8 (eIL-8) production and apoptosis by phenolic metabolites of benzene in HL-60 cells and human bone marrow endothelial cells. 1558 39

4-Anilinoquinazoline derivatives are widely investigated due to their potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. Two 4-anilinoquinazolines with Lavendustin A subunit (10a,b) were synthesized and examined for their EGFR tyrosine kinase inhibitory activity as well as their antiproliferative properties on variant human cancer cell lines. Both compounds maintained their EGFR tyrosine kinase inhibitory activity at the 10-7 M level and led to significant growth inhibition in certain leukemia, non-small cell lung cancer (NSCLC), ovarian cancer, renal cancer and breast cancer cell lines with GI50 values at the 10-6 M level. There could not be observed any notable difference between 10a and 10b regarding to their antiproliferative activity. Interestingly, we observed the high tendency of 10a and 10b to include certain solvents, e.g. water, DMF, DMSO, which may be due to the remarkable number of hydrogen accepting/donating groups in 10a and b. An X-ray analysis of 10a including water and DMF illustrates a possible hydrogen bond pattern and could serve as information for preferred receptor (e.g. EGFR tyrosine kinase) binding sites. Finally, we aimed for irreversible EGFR tyrosine kinase inhibitors. The p-quinone derivatives 11a and 11b, which contain a Michael acceptor position according to the irreversible inhibitor CI-1033, could be derived from the p-hydroquinone derivatives 10a or 10b, respectively, by oxidation. However, due to their instability 11a and 11b could not be obtained in a pure form.
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PMID:4-Anilinoquinazolines with Lavendustin A subunit as inhibitors of epidermal growth factor receptor tyrosine kinase: syntheses, chemical and pharmacological properties. 1557 62

Benzene toxicity is considered to be elicited by its metabolites and phenolic metabolites of benzene are known to induce apoptosis in leukemia cells in culture and in human bone marrow progenitor cells. One potential mechanism of apoptosis induced by benzene metabolites that has not been examined is the production of pro-apoptotic cytokines such as endothelial IL-8 from endothelial cells in bone marrow stroma. In this study, we utilized HL-60 cells which are known to produce the endothelial form of IL-8 (elL-8) and human bone marrow endothelial cells (HBMEC) as model systems. Hydroquinone (HQ), Catechol (Cat) and benzenetriol (BT) all induced eIL-8 production and apoptosis in HL-60 cells. HQ induced a marked 50-70-fold stimulation of eIL-8 levels and HL-60 cells were shown to have the eIL-8 receptor, CXCR I thus enabling an autocrine pathway of apoptosis. However, treatment with recombinant elL-8 failed to induce apoptosis in HL-60 cells as previously reported and antibodies to either IL-8 or CXCRI did not significantly abrogate benzene metabolite-induced apoptosis. HQ and Cat but not BT also induced stimulation of elL-8 production in HBMEC. These data demonstrate that although metabolites of benzene induce marked stimulation of eIL-8, this is unlikely to be responsible for apoptosis induced in HL-60 cells. Our data also demonstrates that phenolic metabolites of benzene stimulate the production of eIL-8 from HBMEC suggesting that higher levels of endothelial-derived cytokines may occur in bone marrow after benzene exposure.
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PMID:Stimulation of endothelial IL-8 (eIL-8) production and apoptosis by phenolic metabolites of benzene in HL-60 cells and human bone marrow endothelial cells. 1535 18


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