Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Exposure to simple aromatic hydrocarbons has been shown to induce P450-dependent activities and the expression of particular P450 isozymes in a manner related to the molecular structure of the inducing hydrocarbon. In an attempt to identify the structural relationship controlling P450 induction, the effect of hydrocarbon treatment on the RNA levels for specific P450 isozymes was examined. 2. Rats were treated with daily injections of hydrocarbons (benzene, toluene, ethylbenzene, n-propylbenzene, m- and p-xylene) for 3 days, and the effects on specific RNA levels were examined by Northern blot hybridization. 3. Although P4502B1 mRNA was not elevated after hydrocarbon treatment, a significant elevation in 2B2 mRNA was observed after exposure to the larger aromatic hydrocarbons, ethylbenzene and m-xylene. It is interesting to note that despite the substantial elevation of P4502B protein levels, only a small elevation of P4502B1 and 2B2 RNA was observed. 4. P4502C11 mRNA was only suppressed by ethylbenzene administration, despite the depression of 2C11 protein levels by several hydrocarbons. 5. P4501A1 mRNA was not detectable and 2E1 mRNA was not changed by any aromatic hydrocarbon treatment investigated in this study. 6. The data indicate that the levels of mRNA species for a number of P450 isozymes are differentially regulated by exposure to hydrocarbons, and that small changes in hydrocarbon size or isomeric structure can influence the levels of these mRNA species.
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PMID:Relationship between hydrocarbon structure and induction of P450: effect on RNA levels. 760 10

Chronic exposure of humans to benzene (BZ), a widely used industrial chemical and a ubiquitous environmental pollutant, causes aplastic anemia and acute myeloid leukemia. The purpose of the studies reported here was to determine whether the observed depression of bone marrow (BM) cellularity in mice administered benzene was reflected in a suppression of development of all of the hematopoietic lineages and to confirm the ability of interleukin-1 alpha (IL-1 alpha) to prevent BZ-induced BM cell depression. We report that BZ, administered twice per day for 2 days to C57B1/6J mice at a dose of 600 mg/kg body weight, caused a significant depression of the total number of nucleated BM cells per femur when measured on day 3. The observed depression reflects a complex situation that represents the net effect of a decrease in the total number of cells of the lymphocytic and erythroid lineages, along with an increase in the number of intermediate and terminally differentiated cells of the granulocytic lineage. An experiment to monitor the effects of BZ over a 7-day period showed a progressive depressive effect on the lymphocytes and an initial depression of the erythroid cells at day 3 that remained constant until day 7. Conversely, the numbers of intermediate and terminally differentiated granulocytes progressively increased over the 7 days. The BM appeared to recover from the depressive effects of BZ immediately upon cessation of exposure, as the number of nucleated BM cells began to rise by day 5 and was equal to that of the control group by day 7. The results expand our earlier finding (Renz and Kalf 1991) that the overall depression of BM cellularity occurs because of an inability of the stromal fibroblast to produce colony-stimulating factors essential for stem and progenitor cell survival. This results from inhibition by the BZ metabolite, hydroquinone (HQ), of the processing of pre-IL-1 alpha to the mature cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A morphological analysis of the short-term effects of benzene on the development of the hematological cells in the bone marrow of mice and the effects of interleukin-1 alpha on the process. 771 69

Benzene is a widely used industrial solvent known to cause bone marrow depression. This is associated with increased production of reactive oxygen metabolites and nitric oxide by bone marrow phagocytes, which have been implicated in hematotoxicity. Benzene metabolism to phenolic intermediates appears to be an important factor in bone marrow toxicity. In the present studies, we compared the effects of benzene and several of its metabolites on nitric oxide production by murine bone marrow leukocytes. Bone marrow cells readily produced nitric oxide in response to the inflammatory mediators lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Treatment of mice with benzene (800 mg/kg), or its metabolites hydroquinone (100 mg/kg), 1,2,4-benzenetriol (25 mg/kg), or p-benzoquinone (2 mg/kg), at doses that impair hematopoiesis, sensitized bone marrow leukocytes to produce increased amounts of nitric oxide in response to LPS and IFN-gamma. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) augmented bone marrow leukocyte production of nitric oxide induced by inflammatory mediators. Benzene, as well as its metabolites, markedly increased the sensitivity of the cells to both GM-CSF and M-CSF. Cells from hydroquinone- or 1,2,4-benzenetriol-treated mice were significantly more responsive to the inflammatory cytokines and growth factors than cells isolated from benzene- or p-benzoquinone-treated mice, suggesting that the phenolic metabolites of benzene are important biological reactive intermediates. Because nitric oxide suppresses cell growth and can be metabolized to mutagens and carcinogens, the ability of benzene and its metabolites to modulates its production in the bone marrow may be important in their mechanism of action.
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PMID:Distinct actions of benzene and its metabolites on nitric oxide production by bone marrow leukocytes. 788 13

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

We have previously shown that transdermal nitroglycerin may induce an increase in the activity of the adrenergic and the renin-angiotensin-aldosterone systems (SRAA) in patients with chronic stable angina pectoris (SA); when the activation of these systems is more pronounced, the antianginal effect of this drug seems to be reduced. The aim of this study was to evaluate the antianginal efficacy of transdermal nitroglycerin administration (TTS-NG 10 mg.24 h-1) in combination with an ACE inhibitor without sulphydryl groups (BNZ, benazepril 10 mg b.i.d.) in respect to placebo, or to TTS-NG or BNZ administered as monotherapy. Twenty-four patients (21M, 3F) were admitted to this multicentre, randomized, double-blind, latin square, placebo-controlled study. Patients received all the treatments (placebo, TTS-NG, BNZ and BNZ + TTS-NG) each for one week; at the end of each week patients performed two exercise tests 2 and 22 h post-dosing. Two hours post-dosing, exercise duration at 1 mm ST depression was significantly increased in respect to placebo during TTS-NG (P < 0.05) and TTS-NG + BNZ (P < 0.05) treatments. Two hours post-dosing, exercise duration at peak exercise was also increased in respect to placebo during TTS-NG (P < 0.05) and TTS-NG + BNZ (P < 0.05); 22 h post-dosing the increase in exercise duration was significant only during TTS-NG + BNZ treatment (P < 0.05) in respect to placebo, but not during TTS-NG given alone. Rate-pressure product at 1 mm ST depression was significantly increased 2 h post-dosing during TTS-NG treatment (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of transdermal nitroglycerin in combination with an ACE inhibitor in patients with chronic stable angina pectoris. 813 70

Nitric oxide is a short-lived reactive mediator that inhibits bone marrow (BM) cell proliferation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF). The present studies show that nitric oxide also inhibits macrophage colony-stimulating factor (M-CSF)-induced growth of mouse BM cells, an effect that was dependent on the presence of an inflammatory mediator and blocked by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMA). Treatment of mice with the hematotoxicant benzene (800 mg/kg, intraperitoneally, two times per day, for 2 days) resulted in a significant increase in nitric oxide production by BM cells stimulated with lipopolysaccharide (LPS) and interferon gamma alone or in combination with M-CSF or GM-CSF. Cells from benzene-treated mice also displayed increased sensitivity to the growth-promoting effects of M-CSF and GM-CSF. These results suggest that benzene treatment of mice primes BM cells to inducers of nitric oxide. Northern blot analysis showed that this was, at least in part, caused by increased expression of mRNA for inducible nitric oxide synthase (iNOS). Surprisingly, treatment of mice with L-NMA was found to cause a depression in BM cell proliferation and to potentiate benzene-induced decreases in BM cellularity and increases in nitric oxide production. L-NMA administration also augmented nitric oxide production by BM cells. These data indicate that L-NMA is hematotoxic and suggest that it may have actions distinct from inhibition of nitric oxide synthase in the BM.
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PMID:Enhanced production of nitric oxide by bone marrow cells and increased sensitivity to macrophage colony-stimulating factor (CSF) and granulocyte-macrophage CSF after benzene treatment of mice. 819 60

Hematologic surveillance data from 1940 to 1975 were analyzed for a benzene-exposed cohort of 459 rubber workers. The present analyses are restricted to 161 workers with "preemployment" counts done before exposure and rely on their subsequent counts from the first 12 months of employment. While blood cell counts declined approximately 1000 cells/mm3 over the first 4 months of exposure. Using repeated-measures analysis of variance, workers exposed above the median benzene exposure at the plant had significantly lower average white and red blood cell counts at each month during the first year of work when compared with workers exposed below the median. These decreased counts suggest that clinically detectable bone marrow depression accompanied the onset of work in this plant during the 1940s and support exposure assessments that favor higher benzene levels in the 1940s when compared with subsequent decades. The general utility of repeated-measures analytic techniques for medical surveillance data is also demonstrated by this analysis.
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PMID:Hematologic effects of benzene. Job-specific trends during the first year of employment among a cohort of benzene-exposed rubber workers. 822 27

Chronic exposure of humans to benzene causes severe bone marrow cell depression leading to aplastic anemia. Marrow stromal macrophage dysfunction and deficient interleukin-1 production has been reported for patients with severe aplastic anemia. The stromal macrophage, a target of benzene toxicity, is involved in hematopoietic regulation through the synthesis of several cytokines including interleukin-1, which is required for production by stromal fibroblasts of a number of cytokines required for the survival of hematopoietic progenitor cells. We have previously demonstrated that hydroquinone, a major toxic metabolite of benzene in marrow, prevents the proteolytic conversion of 31 kDa pre-interleukin-1 alpha to the 17 kDa cytokine by calpain in purified murine stromal macrophages. Furthermore, stromal macrophages from benzene-treated mice produce the 31 kDa pre-interleukin-1 alpha when stimulated in culture with endotoxin, but cannot convert the precursor to interleukin-1 alpha. In this report, we show that 1,4-benzoquinone, the oxidation product of hydroquinone in the cell, causes a concentration-dependent inhibition of highly purified human platelet calpain with an IC50 of 3 microM. Hydroquinone also inhibits the processing of pre-interleukin-1 beta by interleukin-1 beta convertase. The addition of 2 microM hydroquinone to B1 cells that undergo autocrine stimulation by interleukin-1 beta resulted in the cessation of autocrine cell growth and interleukin-1 beta secretion into the culture medium, as determined by Western immunoblots of the culture supernatants. Purified converting enzyme treated with 3 microM benzoquinone was incapable of converting 31 kDa recombinant pre-interleukin-1 beta to the 17 kDa mature cytokine as analyzed by polyacrylamide gel electrophoresis and Western immunoblotting. These findings support our observations in a mouse model that benzene-induced bone marrow cell depression results from a lack of interleukin-1 alpha subsequent to an inhibition by benzoquinone of calpain, the protease required for converting pre-interleukin-1 alpha to active cytokine. The results may provide a basis for studying benzene-induced aplastic anemia in a mouse model.
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PMID:Inhibition of the conversion of pre-interleukins-1 alpha and 1 beta to mature cytokines by p-benzoquinone, a metabolite of benzene. 854 60

The hematotoxic effects of benzene in both humans and animals are well documented. Current estimates concerning the risks associated with benzene exposure are usually based on adult, male cohort studies; however, there are indications that females may respond differently than males to benzene and that fetuses may respond differently than adults. Another factor to be considered in risk estimates is the impact of personal habits. In experimental animals, ethanol consumption is known to increase the hematotoxicity of benzene; therefore, alcohol consumption may also alter the potential risk of individuals exposed to benzene. To address some of the factors that may confound risk estimates for benzene exposure, a series of experiments were performed. Age-matched male as well as pregnant and virgin female Swiss Webster mice were exposed to 10 ppm benzene for 6 h a day over 10 consecutive days (days 6 through 15 of gestation for the pregnant females). Half of the animals also received 5% ethanol in the drinking water during this period. On day 11, bone marrow cells from the adults and liver cells from the fetuses were assayed for the numbers of erythroid colony-forming units (CFU-e). CFU-e assays were also performed on bone marrow cells isolated from 6-week postpartum dams exposed during gestation and from in utero-exposed 6-week old males and females. Gender differences were clearly observed in the responses to the various exposure protocols. Depressions in CFU-e numbers were only seen in male mice while elevations in CFU-e numbers were only seen in female mice. Male mice exposed as adults for 10 days to benzene (B), ethanol (E) or benzene+ethanol (B+E) exhibited depressed CFU-e levels as did male fetal mice exposed to B in utero. In addition, adult male mice which had been exposed in utero to either B or to E individually displayed depressed CFU-e levels. In contrast, none of the groups of female mice exhibited any depressions in CFU-e numbers after any of the exposures. Elevations in CFU-e numbers were observed among pregnant females exposed to E and among adult females exposed to B+E in utero. In summary, a majority (6/9) of the exposure protocols produced depressions in the CFU-e numbers of male mice, whereas a majority (7/9) of the exposure protocols produced no changes in the CFU-e numbers of female mice. Those changes that were observed in females consisted of elevations of CFU-e numbers. These results suggest that the male erythron is more susceptible than the female erythron to the hematotoxicants benzene and ethanol, regardless of whether exposures occur in utero or during adulthood.
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PMID:Influences of gender, development, pregnancy and ethanol consumption on the hematotoxicity of inhaled 10 ppm benzene. 882 79

This case report contains the history of a man's exposure to benzene, trichloroethylene, and toluene. J suffered acutely from classic symptoms of toxic exposure to these compounds, such as fatigue, clumsiness, staggering, and hematopoietic depression. During his medical hospitalization, he was exposed to further organic insults, such as being treated with medications like Cytoxan and medications to treat an abscess in his right parietal lobe. After the acute exposure and after the abscess had resolved, his functioning on neuropsychological testing was still depressed, as he had a Full Scale IQ of 105, whereas at the time of the forensic evaluation he had a Full Scale IQ of 114. It would therefore appear that he did have some mild deficits when originally discharged from the hospital. While he reported having continual mental status changes at the time of the offense and even at the time of the forensic evaluation, it was not felt that these played a significant role in the commission of the offense. Comprehensive forensic evaluation suggested that psychological reactions to his illness and an underlying personality disorder were more direct contributors to the criminal acts. J was therefore recommended and ultimately found to be responsible for his behavior, according to the law.
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PMID:Criminal responsibility and solvent exposure. 893 24


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