Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Occupational exposure to benzene, a major industrial chemical, has been associated with various blood dyscrasias and increased incidence of acute myelogenous leukemia in humans. It is established that benzene requires metabolism to induce its effects. Benzene exposure in humans and animals has also been shown to result in structural and numerical chromosomal aberrations in lymphocytes and bone marrow cells, indicating that benzene is genotoxic. In this review we have attempted to compile the available evidence on the role of increased free radical activity in benzene-induced myelotoxic and leukemogenic effects. Benzene administration to rodents has been associated with increased lipid peroxidation in liver, plasma, and bone marrow, as shown by an increase in the formation of thiobarbituric-acid reactive products that absorb at 535 nm. Benzene administration to rodents also results in increased prostaglandin levels indicating increased arachidonic acid peroxidation. Other evidence includes the fact that bone marrow cells and their microsomal fractions isolated from rodents following benzene-treatment have a higher capacity to form oxygen free radicals. The bone marrow contains several peroxidases, the most prevalent of which is myeloperoxidase. The peroxidatic metabolism of the benzene metabolites, phenol and hydroquinone, results in arachidonic acid peroxidation and oxygen activation to superoxide radicals, respectively. These metabolites, upon co-administration also produce a myelotoxicity similar to that observed with benzene. Recently, we have found that exposure of human promyelocytic leukemia (HL-60) cells (a cell line rich in myeloperoxidase), to the benzene metabolites, hydroquinone and 1,2,4-benzenetriol results in increased steady-state levels of 8-hydroxydeoxyguanosine a marker of oxidative DNA damage. Peroxidatic metabolism of benzene's phenolic metabolites may therefore be responsible for the increased free radical activity and toxicity produced by benzene in bone marrow. We thus hypothesize that free radicals contribute, at least in part, to the toxic and leukemogenic effects of benzene.
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PMID:Potential role of free radicals in benzene-induced myelotoxicity and leukemia. 176 8

Benzene is widely recognized as a leukemogen, and the Occupational Safety and Health Administration is currently attempting to limit exposure to it more strictly. The proposed new regulation is a limit of an eight-hour time-weighted average of 1 ppm in place of the current limit of 10 ppm. The fundamental rationale for the change is a perception that the current standard is associated with an inordinate excess of leukemia. The epidemiologic literature on benzene and leukemia supports the inference that benzene causes acute myelocytic leukemia. However, the available data are too sparse, or suffer other limitations, to substantiate the idea that this causal association applies at low levels (i.e., 1-10 ppm) of benzene. Nonetheless, under the assumption that causation does apply at such low levels, a number of authors, including ourselves, have performed risk assessments using similar data but different methodologies. The assessments that we consider acceptable suggest that, among 1,000 men exposed to benzene at 10 ppm for a working lifetime of 30 years, there would occur about 50 excess deaths due to leukemia in addition to the baseline expectation of seven deaths. However, this estimate is speculative and whether or not enough confidence can be placed in it to justify a lower occupational benzene standard remains a decision for policy makers.
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PMID:Benzene and leukemia. A review of the literature and a risk assessment. 263 57

Rat liver mitochondria incubated with the metabolites of benzene, p-benzoquinone or 1,2,4-benzenetriol, showed a dose-dependent inhibition of [3H]dTTP incorporation into mtDNA with median inhibitory concentrations of 1 mM for each compound. Benzene and the metabolites phenol, catechol and hydroquinone did not inhibit at concentrations up to 10 mM. Similarly, incubation of p-benzoquinone or hydroquinone with rabbit bone marrow mitochondria showed a dose-dependent inhibition of mtDNA synthesis with 50% inhibition at 1 mM and 10 mM, respectively. That these metabolites inhibit mitochondrial replication was evidenced by the fact that [3H]dTTP incorporation into characteristic 38S, 27S and 7S mitochondrial replication intermediates was decreased by the quinones, as analyzed on 5-20% neutral sucrose velocity gradients. p-Benzoquinone, hydroquinone and 1,2,4-benzenetriol inhibited the activity of partially purified rat liver mtDNA polymerase gamma using either activated calf thymus DNA or poly(rA) X p(dT)12-18 as primer/template, with 50% inhibitory concentrations of 25 microM, 25 microM and 180 microM, respectively. Preincubation of the metabolites with polymerase gamma or primer/template, followed by removal of the unreacted metabolite by gel filtration, indicated that inhibition resulted from interaction of the metabolites with the enzyme, rather than with the template. Binding appeared to involve a sulfhydryl residue on the enzyme since the binding of [14C]hydroquinone was prevented by N-ethylmaleimide. The ability of hydroquinone or p-benzoquinone to inhibit binding of [14C]hydroquinone to the enzyme suggests that the compounds bind to a common site or are converted to a common intermediate. Inhibition of, or changes in, replication in mitochondria of bone marrow cells by hydroquinone and p-benzoquinone may explain the changes in the mitochondrial genome observed in marrow stem cells in acute myelogenous leukemia and may suggest a mechanism for benzene leukemogenesis.
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PMID:The inhibition of mitochondrial DNA replication in vitro by the metabolites of benzene, hydroquinone and p-benzoquinone. 400 11

Benzene has the sad privilege of being the only industrial chemical inducing leukemia in susceptible individuals chronically exposed to its vapors. Hence, benzene has been included in the list of human carcinogens. Acute myeloblastic leukemia and erythroleukemia are typical examples of benzene leukemia. Most cases show some features in common: 1) development after many years of exposure and, in some cases many months after leaving the toxic atmosphere; 2) leucopenia or moderate degree of leucocytosis; and 3) splenohepatomegaly discrete or absent. Finding of an antecedent of pancytopenia reinforces the suspicion of benzene as the causative agent. There is still no agreement about the role played by benzene in chronic types of leukemia. In assessing diagnosis of benzene leukemia much importance has been attached by French authors and by myself to the demonstration of benzene in blood or in bone marrow aspirates or biopsies. Treatment of benzene hemopathy based on the oral administration of "anti-benzene compounds" such as methyl-donors and thiol-aminoacids is proposed here based on personal research in rabbits, in leukemic patients treated by benzene in the past and on myself as a volunteer. In pre-leukemic states, lowering the benzene burden of the bone marrow might prevent the further development of acute leukemia. Recently, I found out that: 1) benzene can be converted to phenol in the bone marrow independently of liver oxidizing enzymes; 2) benzene injected in the femoral artery of the rabbit can provoke histological changes at the isolated tibial marrow.
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PMID:An hypothesis for the induction of leukemia by benzene. 657 48

Although benzene is best known as a compound that causes bone marrow depression leading to aplastic anemia in animals and humans, it also induces acute myelogenous leukemia in humans. The epidemiological evidence for leukemogenesis in humans is contrasted with the results of animal bioassays. This review focuses on several of the problems that face those investigators attempting to unravel the mechanism of benzene-induced leukemogenesis. Benzene metabolism is reviewed with the aim of suggesting metabolites that may play a role in the etiology of the disease. The data relating to the formation of DNA adducts and their potential significance are analyzed. The clastogenic activity of benzene is discussed both in terms of biomarkers of exposure and as a potential indication of leukemogenesis. In addition to chromosome aberrations, sister chromatid exchange, and micronucleus formation, the significance of chromosomal translocations is discussed. The mutagenic activity of benzene metabolites is reviewed and benzene is placed in perspective as a leukemogen with other carcinogens and the lack of leukemogenic activity by compounds of related structure is noted. Finally, a pathway from exposure to benzene to eventual leukemia is discussed in terms of biochemical mechanisms, the role of cytokines and related factors, latency, and expression of leukemia.
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PMID:A perspective on benzene leukemogenesis. 794 90

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia and pancytopenia, and acute myelogenous leukemia. A combination of metabolites (hydroquinone and phenol for example) is apparently necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Since benzene and its hydroxylated metabolites (phenol, hydroquinone and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus, the potential exists for competition among various enzymes for phenol. However, zonal localization of Phase I and Phase II enzymes in various regions of the liver acinus regulates this competition. Biologically-based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans.
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PMID:Benzene: a case study in parent chemical and metabolite interactions. 857 60

A large cohort study of 74,828 benzene-exposed and 35,805 unexposed workers employed between 1972 and 1987 in 12 cities in China were followed to determine mortality from all causes and the incidence of lymphohematopoietic malignancies and other hematologic disorders. Benzene-exposed study subjects were employed in a variety of occupations, including painting, printing, and the manufacture of footwear, paint, and other chemicals. All-cause mortality was similar in the benzene-exposed and unexposed comparison group. Statistically significant excess deaths were noted among benzene-exposed subjects for leukemia (RR = 2.3, 95% CP 1.1-5.0), malignant lymphoma (RR = 4.5, 95% CI: 1.3-28.4), and nonneoplastic diseases of the blood (RR = 95% CP 2.5-infinity), and a marginally significant excess was noted for lung cancer (RR = 1.4, 95% CI: 1.0-2.0). Risk was significantly elevated for the incidence of all lymphohematopoietic malignancies (RR = 2.6, 95% CI: 1.5-5.0), malignant lymphoma (RR = 3.5, 95% CI: 1.2-14.9), and leukemia (RR = 2.6, 95% CI.. 1.3-5.7). Among the leukemia subtypes, only acute myelogenous leukemia (AML) incidence was significantly elevated (RR = 3.1, 95% CI: 1.2-10.7), although nonsignificant excesses were also noted for chronic myelogenous leukemia (CML) (RR = 2.6, 95% CI: 0.7-16.9) and lymphocytic leukemias (RR = 2.8, 95% CI.. 0.5-54.5). Significant excesses were found for aplastic anemia (RR = infinity, 95% CI: 2.2-co) and myelodysplastic syndrome (RR = infinity, 95% CI: 1.7-infinity). Employment in benzene-associated occupations in China is associated with a wide spectrum of myelogenous and lymphocytic malignant diseases and related disorders. Investigations continue to assess the nature of these associations.
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PMID:A cohort study of cancer among benzene-exposed workers in China: overall results. 883 74

Chronic exposure of humans to benzene causes acute myelogenous leukemia (AML). The studies presented here were undertaken to determine whether benzene, or its reactive metabolite, hydroquinone (HQ), affects differentiation of myeloblasts. Benzene or HQ administered to C57BL/6J mice specifically induced granulocytic differentiation of myeloblasts. The ability of these compounds to induce differentiation of the myeloblasts was tested directly using the murine interleukin 3 (IL-3)-dependent 32D.3 (G) myeloblastic cell line, and the human HL-60 promyelocytic leukemia cell line. We have previously shown that benzene treatment of HL-60 myeloblasts activates protein kinase C (PKC) and upregulates the 5-lipoxygenase (LPO) pathway for the production of leukotriene D4 (LTD4), an essential effector or granulocytic differentiation. Differentiation was prevented by sphinganine, a PKC inhibitor, and, as shown here, by LPO inhibitors and LTD4 receptor antagonists. Benzene or HQ also induces differentiation in 32D.3 (G) myeloblasts. Both compounds interact with cellular signaling pathways normally activated by granulocyte colony stimulating factor (G-CSF) and can replace the requirement for G-CSF. While IL-3 induces a growth response in 32D.3 (G) cells, G-CSF has been shown to provide both growth and differentiated signals. Both HQ and LTD4 induce differentiation and synergize with IL-3 for growth; however, neither supports growth in the absence of IL-3. Benzene, like HQ, also provides a differentiation signal for 32D cells; however, it has no effect on their growth. Unlike G-CSF, benzene, or LTD4, each of which stimulates terminal differentiation; HQ blocks differentiation at the myelocyte stage, allowing only a small percentage of progenitors to proceed to mature segmented granulocytes. Benzene- and G-CSF-induced differentiation were prevented by the additional of either LPO inhibitors or LTD4 receptor antagonists, indicating that benzene, like G-CSF, upregulates LTD4 production. Hydroquinone-induced differentiation was not affected by the LPO inhibitors, but only by the specific receptor antagonists. Thus HQ appears to obviate the requirement for LTD4 by activating the LTD4 receptor directly.
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PMID:Induction of granulocytic differentiation in a mouse model by benzene and hydroquinone. 911 2

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

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia, pancytopenia, and acute myelogenous leukemia. However, the risks of leukemia at low exposure concentrations have not been established. A combination of metabolites (hydroquinone and phenol, for example) may be necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Because benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol, and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus the potential exists for competition among various enzymes for phenol. Zonal localization of phase I and phase II enzymes in various regions of the liver acinus also impacts this competition. Biologically based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans.
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PMID:Mechanistic considerations in benzene physiological model development. 911 26


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