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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Carcinogenesis 1993 Dec
PMID:Benzene and phenol metabolism by mouse and rat liver microsomes. 826 15

Benzene, a ubiquitous environmental pollutant, is known to cause leukemia and aplastic anemia in humans and hematotoxicity and myelotoxicity in rodents. Toxicity is thought to be exerted through oxidative metabolites formed in the liver, primarily via pathways mediated by cytochrome P450 2E1 (CYP2E1). Phenol, hydroquinone and trans-trans-muconaldehyde have all been hypothesized to be involved in benzene-induced toxicity. Recent reports indicate that benzene oxide is produced in vitro and in vivo and may be sufficiently stable to reach the bone marrow. Our goal was to improve existing mathematical models of microsomal benzene metabolism by including time course data for benzene oxide, by obtaining better parameter estimates and by determining if enzymes other than CYP2E1 are involved. Microsomes from male B6C3F1 mice and F344 rats were incubated with [(14)C]benzene (14 microM), [(14)C]phenol (303 microM) and [(14)C]hydroquinone (8 microM). Benzene and phenol were also incubated with mouse microsomes in the presence of trans-dichloroethylene, a CYP2E1 inhibitor, and benzene was incubated with trichloropropene oxide, an epoxide hydrolase inhibitor. These experiments did not indicate significant contributions of enzymes other than CYP2E1. Mathematical model parameters were fitted to rodent data and the model was validated by predicting human data. Model simulations predicted the qualitative behavior of three human time course data sets and explained up to 81% of the total variation in data from incubations of benzene for 16 min with microsomes from nine human individuals. While model predictions did deviate systematically from the data for benzene oxide and trihydroxybenzene, overall model performance in predicting the human data was good. The model should be useful in quantifying human risk due to benzene exposure and explicitly accounts for interindividual variation in CYP2E1 activity.
Carcinogenesis 1999 Aug
PMID:Use of a mathematical model of rodent in vitro benzene metabolism to predict human in vitro metabolism data. 1042

Fanconi anemia (FA) is a genetic disorder that leads to aplastic anemia and birth defects and predisposes to cancer. FA cells exhibit characteristic hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and FANCG is one of six known FA gene products. By immunocytochemical analysis of transfected cells, we discovered that although FANCG localized to both the nucleus and cytoplasm, there was an increase in cells with predominantly cytoplasmic staining after treatment with MMC. Concurrently, while searching by two-hybrid analysis for proteins that associate with FANCG, we identified a novel interaction between FANCG and cytochrome P450 2E1 (CYP2E1). A member of the P450 superfamily, CYP2E1 is associated with the production of reactive oxygen intermediates and the bioactivation of carcinogens. High constitutive levels of CYP2E1 were found in a FA-G lymphoblast cell line, whereas complementation of the FA-G line with wild-type FANCG was associated with decreased CYP2E1. These findings suggested that the interaction of FANCG with CYP2E1 might alter redox metabolism and increase DNA oxidation. Using a fluorescent assay, we found a dose-dependent increase in the oxidized DNA base, 8-oxoguanine (8-oxoG), after treatment of mutant FA-G cells with H(2)O(2) or MMC. Conversely, significantly lower levels of 8-oxoG were detected in FANCG-complemented FA-G cells. We conclude that the unknown function of FANCG involves at least transient interaction with cytoplasmic components, possibly including CYP2E1, and propose a role for FANCG in protection against oxidative DNA damage.
Carcinogenesis 2002 Jan
PMID:The FANCG Fanconi anemia protein interacts with CYP2E1: possible role in protection against oxidative DNA damage. 1175 25

Telomerase is a ribonucleoprotein (RNP) required for maintenance of telomeres. Although up-regulated telomerase activity is closely linked to the cellular immortality characteristic of late stage carcinogenesis, recently, mutations in the telomerase RNA gene in humans have been associated with dyskeratosis congenita and aplastic anemia, both typified by impaired haemopoietic function. These mutations include base changes in a highly conserved putative telomerase RNA pseudoknot. Here, by using in vitro telomerase assays, NMR, and UV absorbance melting analyses of model oligonucleotides designed to form a "trans-pseudoknot," we describe functional, structural, and energetic properties of this structure. We demonstrate that the pseudoknot domain exists in two alternative states of nearly equal stability in solution: one is the previously proposed pseudoknot formed by pairing P3 with the loop domain of P2b, and the other is a structured P2b loop alone. We show that the two-base mutation (GC1078 --> AG) present in one gene copy in a family with dyskeratosis congenita abrogates telomerase activity. This mutation hyperstabilizes the P2b intraloop structure, blocking pseudoknot formation. Conversely, when the P3 pseudoknot pairing is hyperstabilized by deleting a conserved bulge in P3, telomerase activity also decreases. We propose that the P2bP3 pseudoknot domain acts as a molecular switch, and interconversion between its two states is important for telomerase function. Phylogenetic covariation in the P2b and P3 sequences of 35 species provides a compelling set of "natural" compensatory base pairing changes supporting the existence of the crucial molecular switch.
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PMID:A molecular switch underlies a human telomerase disease. 1248 36

The NBS1 gene is strongly linked to several factors involved in genome integrity. Functional disruption of NBS1 could therefore induce genomic instability and carcinogenesis. Four children with acute lymphoblastic leukemia have been reported to be heterozygous for a germline and/or somatic missense mutation in NBS1, leading to the I171V substitution. We screened healthy controls and pediatric patients with hematological malignancies and aplastic anemia (AA) for the presence of I171V. Of the 62 patients, one individual with AA was confirmed to harbor a homozygous I171V mutation. Genetic analysis of NBS1 in this patient and her healthy parents indicated that she inherited the germline I171V mutation from her father and the wild-type allele from her mother, and that the second I171V hit occurred on the wild-type allele early in embryonic development. Furthermore, cytogenetic analysis of lymphoblastic cell lines from the patient indicated a remarkable increase in numerical and structural chromosomal aberrations in the absence of clastogens, suggesting that she potentially carried genomic instability. This is the first report of AA with a homozygous I171V mutation. We hypothesize that NBS1 may play an important role in the pathogenesis of AA.
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PMID:First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability. 1533 73

2,4,6-Trinitrotoluene (TNT) is an important occupational and environmental pollutant. In TNT exposed humans, the notable toxic manifestations have included aplastic anemia, toxic hepatitis, cataract, hepatomegaly and liver cancer. Therefore, we developed methods to biomonitor workers exposed to TNT. The workers were employed in a typical ammunition factory in China. The controls were recruited from the same factory. We determined hemoglobin (Hb) adducts and urine metabolites of TNT. Hb-adducts of TNT, 4-amino-2,6-dinitrotoluene (4ADNT) and 2-amino-4,6-dinitrotoluene (2ADNT), and the urine metabolites of TNT, 4ADNT and 2ADNT were found in all the workers and in a few controls. 4ADNT was the main product. Although the levels of 2ADNT correlated well with 4ADNT, 2ADNT was not found in all the samples. Therefore, 4ADNT was the best marker of exposure for Hb-adducts and urine metabolites. The levels of the urine metabolites and Hb-adducts were related to the health status of the workers. The Hb-adduct 4ADNT was statistically significantly associated with risk of hepatomegaly, splenomegaly and cataract. The odds ratio (OR) for cataract, splenomegaly and hepatomegaly were 6.4 [95% confidence interval (CI) = 1.4-29.6], 9.6 (1.1-85.3) and 7.6 (1.3-43.7), respectively. No correlation was found between urine metabolites and health effects. These results were tested for confounding factors like age, workyears, smoker status, smoke years, cigarettes per day and hepatitis B status using stepwise forward logistic regression analysis. In the case of splenomegaly, hepatitis B status is a confounder. In the case of cataract, age is a confounder. The Hb-adduct, 4ADNT, is a good biomarker of exposure and biomarker of biological effect.
Carcinogenesis 2005 Jul
PMID:Hemoglobin adducts, urinary metabolites and health effects in 2,4,6-trinitrotoluene exposed workers. 1581 13

Telomerase is critical for the integrity of stem cell compartments. Mutations in telomerase components lead to telomere shortening and hematopoietic stem cell failure in autosomal dominant dyskeratosis congenita and aplastic anemia. Telomerase activity is readily detected in most cancers but not in adult somatic cells. The telomere hypothesis for cancer states that telomerase is reactivated in late stages of carcinogenesis. However, recent evidence has suggested a stem cell origin for certain cancers, implying that the genetic alterations that lead to cancer accumulate in tissue-specific stem cells and not in adult somatic cells. In these cancers, stem cells would already have telomerase and it would not need to be reactivated. Here, we reconsider the telomere hypothesis in view of this evidence and propose that, rather than telomerase reactivation, enzyme activity may increase in later stages of carcinogenesis due to increased expression or efficient assembly of telomerase components. Understanding these mechanisms will refine approaches to telomerase inhibition in cancer.
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PMID:Telomerase and cancer stem cells. 1686 55

Hydroquinone has been used for decades as a skin lightening agent. Since January 1, 2001, its use in cosmetics has been banned. This ban is as a result of mid-term effects such as leukoderma-en-confetti/occupational vitiligo and exogenous ochronosis. However, a recent literature search on hydroquinone as a skin lightening agent suggests that possible long-term effects such as carcinogenesis may be expected as well. Metabolites of hydroquinone formed in the liver, e.g., p-benzoquinone and glutathione conjugates of hydroquinone, are mainly responsible for this. In the bone marrow, hydroquinone is oxidized into p-benzoquinone because of the high myeloperoxidase activity. Topically applied hydroquinone-containing creams may give rise to accumulation of these compounds, which can cause DNA damage and mutations. They also have the capability to disrupt protective mechanisms, whereby they facilitate further development of cancer. In the bone marrow, long-term effects such as aplastic anemia and acute myeloid leukemias may occur. Most of the evidence stems from research on benzene toxicity, which appears to arise via its metabolite hydroquinone. There is no report yet demonstrating carcinogenesis resulting from the application of hydroquinone-containing creams. However doctors should be aware of these potential health risks which were up until now disregarded.
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PMID:Hydroquinone and its analogues in dermatology - a potential health risk. 1717 92

Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest-lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis. The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients be categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.
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PMID:The role of telomere biology in bone marrow failure and other disorders. 1816 98

Human telomeres (discovery of telomere structure and function has been recently awarded The Nobel Prize) consist of approximately 5-12 kb of tandem repeated sequences (TTAGGG)n and associated proteins capping chromosome ends which prevent degradation, loss of genetic information, end-to-end fusion, senescence and apoptosis. Due to the end-replication problem, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence when telomeres become critically short. Stabilization of the telomeric DNA through telomerase activation, unique reverse transcriptase, or activation of the alternative mechanism of telomere maintenance is essential if the cells are to survive and proliferate indefinitely. Telomerase is expressed during early development and remains fully active in specific germline cells, but is undetectable in most normal somatic cells. High level of telomerase activity is detected in almost 90% of human tumours and immortalized cell lines. The hematopoietic compartment may develop genetic instability as a consequence of telomere erosion, resulting in aplastic anaemia (AA) and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Genetic instability associated with telomere dysfunction (i.e. short telomeres) is an early event in carcinogenesis. The molecular cytogenetic method telomere/centromere fluorescence in situ hybridization (T/C-FISH) can be used to characterize the telomere length of hematopoietic cells. This review describes recent advances in the molecular characterization of telomere system, the regulation of telomerase activity in cancer pathogenesis and shows that the telomeric length could be a potential clinical marker of hematologic neoplasia and prognosis of disease.
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PMID:The role of telomeres and telomerase complex in haematological neoplasia: the length of telomeres as a marker of carcinogenesis and prognosis of disease. 2065 99


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