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 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

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

Benzene is a ubiquitous, highly flammable, colorless liquid that is a known hematotoxin, myelotoxin, and human leukemogen. Benzene-induced toxicity in animals is clearly mediated by its metabolism. The mechanisms of acute hemato- and myelotoxicity in humans are almost certainly the same as in animals, and there is compelling evidence that metabolism is requisite for the induction of leukemia in humans. A very large number of experimental investigations of benzene metabolism have been conducted with animals, both in vivo and in vitro. There have also been many investigations of benzene metabolism in humans and with human tissues, Although the blood or tissue concentrations of benzene metabolites in humans resulting from benzene exposure have never been measured. Further, a number of mathematical models of benzene metabolism and dosimetry have been developed. In this article, we consider results from both experimental and mathematical modeling research, with particular emphasis on the last decade, and discuss the factors that are likely to be most influential in the metabolism of benzene.
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PMID:A review of quantitative studies of benzene metabolism. 1140 42

Benzene is an established cause of human leukemia that is thought to act by producing chromosomal aberrations and altered in cell differentiation. In several recent studies increased levels of chromosomal aberrations in peripheral blood lymphocytes were correlated with a heightened risk of cancer, especially hematological malignancies. Thus, chromosomal aberrations may be a predictor of future leukemia risk. Previous studies exploring whether benzene exposure induces chromosomal aberrations have yielded mostly positive results. However, it remains unclear whether the chromosomal aberrations induced by benzene occur in a distinct pattern. Here, we thoroughly review the major chromosome studies published to date in benzene-exposed workers, benzene-poisoned and preleukemia patients, and leukemia cases associated with benzene expose. Although three cytogenetic markers (chromosomal aberrations, sister chromatid exchanges, and micronuclei) are commonly examined, our primary focus is on studies of chromosomal aberrations, because only this marker has so far been correlated with increased cancer risk. This review surveys the published literature, analyzes the study results, and discusses the characteristics of effects reported. In most studies of currently exposed workers, increases in chromosomal aberrations were observed. However, due to the relatively small number of affected individuals and variability in the reported aberrations, firm conclusions cannot be made about the involvement of specific chromosomes or chromosome regions. Further, in leukemia cases associated with benzene exposure, there is no evidence of a unique pattern of benzene-induced chromosomal aberrations in humans. Leukemia cases associated with benzene exposure are, however, more likely to contain clonal chromosome aberrations then those arising de novo in the general population.
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PMID:The nature of chromosomal aberrations detected in humans exposed to benzene. 1184 14

Acute myeloid leukaemia (AML) cases with different chromosomal abnormalities may reflect different aetiologies. Benzene exposure, from a number of sources including smoking, is one risk factor for AML. Individual susceptibility to benzene may depend on differences in expression of metabolizing enzymes. We tested the hypothesis that smoking as well as genetic polymorphisms in the microsomal epoxide hydrolase gene (HYL1), an enzyme involved in benzene metabolism, could be risk factors for AML with defined chromosomal abnormalities. Twenty-six AML cases with -7/del(7q) and 24 cases with t(8;21), as well as 43 cases with normal karyotype and 155 age-, sex- and residence-matched controls, were drawn from a large case-control study on adult acute leukaemia. Current smoking was significantly associated with the cytogenetic abnormalities t(8;21) or -7/del(7q) (OR = 4.9; 95%CI = 2.1-11.5) but not with a normal karyotype, relative to individuals who were not current smokers. A putative high activity HYL1 phenotype [exon 3, residue 113 (Tyr/Tyr) and exon 4, residue 139 (His/Arg or Arg/Arg)] was associated with a significantly increased AML risk in men with -7/del(7q) or t(8;21) (OR = 4.4; 95%CI 1.1-17.0) but not with a normal karyotype. This suggests that AML cases with defined chromosomal abnormalities could be related to specific carcinogen exposures and, furthermore, suggests that smoking and genetic polymorphisms in HYL1 could be risk factors for AML with -7/del(7q) or t(8;21).
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PMID:Genetic polymorphisms in microsomal epoxide hydrolase and susceptibility to adult acute myeloid leukaemia with defined cytogenetic abnormalities. 1184 15

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

Genetic approaches to understanding the etiology of the acute leukemias are beginning to deliver meaningful insights. Polymorphic variants in xenobiotic metabolizer loci were a natural starting point to study the relevance of these changes. The finding that glutathione S-transferase (GST) T1 null variants increase leukemia risk has implicated oxidative stress in hematopoietic stem cells as an important etiological factor in acute myeloid leukemia (AML). The importance of these enzyme systems in handling specific substrates has also been confirmed by the finding of an increased risk of therapy-related leukemia in individuals with underactive variants of GSTP1 who have been exposed to a chemotherapeutic agent metabolized by this enzyme. Benzene is a well-recognized leukemogen, and genetic variants in its metabolic pathway can modulate the risk of leukemia following exposure. In particular, underactive variants of the NAD(P)H:quinone oxidoreductase 1 gene (NQO1) seem to increase the risk of AML. Other enzymes within the pathway are proving more difficult to study because of the absence of variants that significantly affect the biological activity of the enzyme under study. No effect of the myeloperoxidase (MPO) gene variants in altering the risk of AML has been seen in our studies. Another pathway recently shown to be important in determining leukemia risk is folic acid metabolism, particularly important in predisposition to acute lymphocytic leukemia (ALL). Polymorphic variants of the methylenetetrahydrofolate reductase gene (MTHFR) which impair its activity have been shown to be associated with a protective effect. This is thought to be due to an increased availability of nucleotide precursors for incorporation into DNA. This finding implicates misincorporation of uracil into DNA as an important mechanism of leukemic change in lymphoid precursors. Future studies will extend these observations but will require biological material collected from large well-controlled epidemiological studies. The technological challenges imposed by the high throughput of samples required by these studies are currently being addressed.
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PMID:Metabolic enzyme polymorphisms and susceptibility to acute leukemia in adults. 1208 44

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

Carcinogenesis is a multi-stage and prolonged process. At the present time, our knowledge of biological activities along the process is incomplete, therefore, a variety of experimental data are used to assess health risk from exposure to environmental chemicals. However, experimental approaches may not be adequate unless human data are available to support the assessment. In this brief review, benzene (CAS No. 71-43-2), a well-established human leukemogen, will be used as an example to illustrate the challenge in assessing toxicological mechanisms and cancer risk. Benzene has been shown to form DNA-adducts in experimental animals but the adducts have proved elusive of detection in human. Several toxic metabolites of benzene have been identified but the metabolite(s) responsible for the carcinogenic activities is unknown. Furthermore, the significant differences between rodents and human in response to benzene exposure are not understood. Therefore, the bone marrow specificity for the induction of leukemia in human by benzene remains to be elucidated. These complications illustrate the complexity of the assessment process and identify serious information gaps. These information gaps can be viewed as research opportunities to provide more precise data for assessment of toxicological effects and health risk.
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PMID:Assessing DNA damage and health risk using biomarkers. 1242 36

Benzene is one of wildly used chemicals. Long-term exposure to benzene causes hematotoxicities and further, the development of including anemia, myelodysplastic syndrome (MDS), aplastic anemia, etc., with the leukemia as the worst. People vary greatly in their susceptibility to adverse health outcomes from benzene exposure. The author reviewed the relationship between genetic polymorphism of I metabolic enzymes(CYP2E1, NQO1, MPO) and II metabolic enzymes(GST, PST) involving benzene metabolite and interindividual variation in their genetic susceptibility to hematotoxicity from benzene exposure in this paper.
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PMID:[Individual susceptibility to hematotoxicity from benzene exposure and the genetic polymorphism of metabolic enzymes]. 1256 53


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