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 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene toxicity involves both bone marrow depression and leukemogenesis caused by damage to multiple classes of hematopoietic cells and a variety of hematopoietic cell functions. Study of the relationship between the metabolism and toxicity of benzene indicates that several metabolites of benzene play significant roles in generating benzene toxicity. Benzene is metabolized, primarily in the liver, to a variety of hydroxylated and ring-opened products that are transported to the bone marrow where subsequent secondary metabolism occurs. Two potential mechanisms by which benzene metabolites may damage cellular macromolecules to induce toxicity include the covalent binding of reactive metabolites of benzene and the capacity of benzene metabolites to induce oxidative damage. Although the relative contributions of each of these mechanisms to toxicity remains unestablished, it is clear that different mechanisms contribute to the toxicities associated with different metabolites. As a corollary, it is unlikely that benzene toxicity can be described as the result of the interaction of a single metabolite with a single biological target. Continued investigation of the metabolism of benzene and its metabolites will allow us to determine the specific combination of metabolites as well as the biological target(s) involved in toxicity and will ultimately lead to our understanding of the relationship between the production of benzene metabolites and bone marrow toxicity.
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PMID:An overview of benzene metabolism. 911 88

The aggregation and interface behavior of alkyltrimethylammonium bromides (CnH2n+1(CH3)3N+Br-: CnTMA with n = 14, 16, 18) have been investigated in concentrated orthophosphoric acid by means of surface tension measurements. Adsorption of these cationic surfactants at the interface between air and aqueous H3PO4 solutions has been determined at 298 K using the Wilehlmy plate method. Measurements in the most concentrated H3PO4-H2O mixture (95% by weight of acid or 17.5 mol/L) were done at the n-decane/H3PO4 interface using the ring method to avoid any contamination with atmospheric moisture. The critical micelle concentration (CMC), the maximum surface concentration, and surface pressure of C16TMA in water-H3PO4 mixtures and of the homologous series of surfactants, CnTMA, in 95%-H3PO4, were determined at 323 K. Benzene has been used as a test solute for solubilization measurements in 95%-H3PO4 containing C16 TMA micelles. From this experimental work, it can be concluded that micelles are forming even in the most concentrated solutions in acid and that the CMC displays a large depression between 4 and 10 mol/L of H3PO4. The maximum surface concentration increases by steps in the lowest (0 to 1 mol/L) and highest range of concentration (8 to 10 mol/L) in acid. The Klevens equation relating the CMC in relation to the chain length of the surfactants holds in 95%-H3PO4. Values obtained for the parameters of the Klevens equation and for the free energy of micellization in 95%-H3PO4 have been compared to other strongly acidic media like concentrated sulfuric or methanesulfonic acids. Copyright 1998 Academic Press.
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PMID:Surface Activity of n-Alkyltrimethylammonium Bromides in Concentrated Orthophosphoric Acid. 971 Apr 96

Increased levels of DNA-protein cross-links (DNAPC) have been observed in vitro and in vivo following treatment with a number of chemotherapeutic alkylating agents and topoisomerase II inhibitors, that is, agents that have also been associated with the development of bone marrow depression and acute myelogenous leukemia. The current studies were undertaken to examine the effect of benzene, a bone marrow toxin and human leukemogen, on DNAPC levels in mouse bone marrow cells. Using a K+/sodium dodecyl sulfate (SDS) precipitation assay for DNAPC determination, the results indicate increased DNA-protein cross-link levels in mouse bone marrow cells at 2 and 4 but not 8 h after a single ip injection of 440 mg/kg benzene. Following the administration of multiple hematotoxic benzene doses (440 or 880 mg/kg, 2x/d for 2 d), increases in DNA-protein cross-link levels were either slight or not present. These results suggest that DNAPC induced by benzene are neither cumulative nor persistent lesions. The toxicity of benzene is mediated by a number of number of ring-hydroxylated and ring-opened compounds; therefore the present studies also examined DNAPC levels in mice administered trans,trans-muconaldehyde (MUC), a ring-opened hematotoxic and genotoxic metabolite of benzene. No marked increases in DNAPC levels were observed in CD- mouse bone marrow cells 1-12 h following a single ip injection of 3 mg/kg muconaldehyde. It is possible that multiple doses of MUC are required to induce elevated DNAPC levels in bone marrow cells of mice, since multiple doses are required for MUC-induced hematotoxicity. Other reactive metabolites and/or an interaction of reactive intermediates may also be involved in DNAPC induced by benzene.
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PMID:DNA-protein cross-link levels in bone marrow cells of mice treated with benzene or trans,trans-muconaldehyde. 1009 61

A young woman committed suicide by ingesting benzine. We report the findings obtained at autopsy and the chemical analyses of the gastric contents, blood, and tissues in this case. Fatal concentrations of n-hexane, benzene, toluene and m-, p-xylene were detected. Pulmonary edema and hemorrhage were caused by the primary effect of the chemicals or secondarily by respiratory depression, suffocation due to volatile fluid, or heart failure. Mild hemorrhage around arterioles and venules in the brain cortex suggest hyperpermeability of the vessels. The fragmentation and waviness of the cardiac myofibrils indicate the presence of hypercontraction and possibly arrhythmia.
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PMID:A fatal case of oral ingestion of benzine. 1020 45

A previous report from this laboratory focused on the metabolism of [14C]benzene (BZ) in the isolated, perfused, mouse liver (C. C. Hedli, et al., 1997, Toxicol. Appl. Pharmacol. 146, 60-68). Whereas administration of BZ to mice results in bone marrow depression (R. Snyder et al., 1993, Res. Commun. Chem. Pathol. Pharmacol. 20, 191-194), administration of phenol (P), the major metabolite of BZ, does not. It was, therefore, of interest to determine whether the metabolic fate of P produced during BZ metabolism differed from that of P metabolized in the absence of BZ. Mouse livers were perfused with a solution of [14C]P in both the orthograde (portal vein to central vein) and retrograde (central vein to portal vein) direction to investigate the metabolic zonation of enzymes involved in P hydroxylation and conjugation. Perfusate samples were collected, separated by HPLC, and tested for radioactivity. Unconjugated metabolites were identified by comparing their retention times with nonradiolabeled standards, which were detected by UV absorption. Conjugated metabolites were identified and collected on the basis of radiochromatogram results, hydrolyzed enzymatically, and identified by co-chromatography with unlabeled BZ metabolites. The objective was to compare and quantify the metabolites formed during the perfusion of P in the orthograde and retrograde directions and to compare the orthograde P-perfusion results with the orthograde BZ results reported previously. Regardless of the direction of P perfusion, the major compounds released from the liver were P. phenylgucuronide, phenylsulfate, hydroquinone (HQ), and HQ glucuronide. A comparison of the results of perfusing P in the orthograde versus the retrograde direction showed that more P was recovered unchanged and more HQ was formed during retrograde perfusion. The results suggest that enzymes involved in P hydroxylation are generally closer to the central vein than those involved in conjugation, and that during retrograde perfusion, P metabolism may be limited by the sub-optimal conditions of perfusion. Comparison of the orthograde perfusion studies of P and BZ revealed that a larger percentage of the radioactivity released from the liver was identified as unconjugated HQ after BZ perfusion than after P perfusion. In addition, the amount of radioactivity covalently bound to liver macromolecules was measured after each perfusion and determined to be proportional to the amount of HQ and HQG detected in the perfusate samples.
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PMID:Metabolism of [14C]phenol in the isolated perfused mouse liver. 1036 40

In vitro cloning assays for hematopoietic myeloid and erythroid precursor cells have been used as screening systems to investigate the hematotoxic potential of environmental chemicals in humans and mice. Granulocyte-monocyte progenitors (CFU-GM) from human umbilical cord blood and from mouse bone marrow (Balb/c and B6C3F1) were cultured in the presence of lead and the benzene metabolite catechol. Erythroid precursors (BFU-E) from human umbilical cord blood were cultured in the presence of lead. The in vitro exposure of the human and murine cells resulted in a dose-dependent depression of the colony numbers. The concentration effect relationship was studied. Results showed that: (1) Based on calculated IC50 values, human progenitors are more sensitive to lead and catechol than are murine progenitors. The dose that caused a 50% decrease in colony formation after catechol exposure was 6 times higher for murine cells (IC50 = 24 micromol/L) than for human cord blood cells (IC50 = 4 micromol/L). Lead was 10-15 times more toxic to human hematopoietic cells (IC50 = 61 micromol/L) than to murine bone marrow cells from both mice strains tested (Balb/c, IC50 = 1060 micromol/L; B6C3F1, IC50 = 536 micromol/L). (2) A lineage specificity was observed after exposure to lead. Human erythroid progenitors (hBFU-E) (IC50 = 3.31 micromol/L) were found to be 20 times more sensitive to the inhibitory effect of lead than were myeloid precursors (hCFU-GM) (IC50 = 63.58 micromol/L). (3) Individual differences in the susceptibility to the harmful effect of lead were seen among cord blood samples. (4) Toxicity of lead to progenitor cells occurred at environmentally relevant concentrations.
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PMID:Lead and catechol hematotoxicity in vitro using human and murine hematopoietic progenitor cells. 1040 57

PCBs are a family of 209 chemical compounds, each of which consists of two benzene rings and 1 to 10 chlorine atoms. Their long-term stability and dispersion into the environment and the food chain have caused concern about their impact on humans and the environment. Native American communities are believed to be at particularly high risk of such exposure since they typically are more dependent than other populations on local fish and game as a food source. We have evidence for a significant excess in incidence and prevalence of hypothyroidism among Mohawks, particularly older women, as compared to other populations. The goal of the current project is to compare serum PCB concentrations to indicators of thyroid function in controls and patients with demonstrated thyroid dysfunction. Studies on experimental animals (rats) have shown significant depression of circulating levels of T4 and moderate reductions in levels of T3 after exposure to PCBs. We are conducting a retrospective observational case-control study. The participants are Mohawk women 30 years of age and older. Controls are participants in an ongoing environmental epidemiology study, whose thyroid hormone tests show a normal function. Our study aims to investigate the association between long-term exposure to PCBs and acquired hypothyroidism, to identify the critical exposure routes and to develop and apply toxic equivalents for thyroid disease for the various PCB congeners. PCB exposure is assessed by ultra-trace, congener-specific determination in blood specimen using GC/ECD. The study is currently ongoing. We have analyzed 46 samples of cases and 75 samples of controls.
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PMID:The assessment of risk to acquired hypothyroidism from exposure to PCBs: a study among Akwesasne Mohawk women. 1096 41

Thermoanalytical, chromatographic, and microscopic methods of analysis were used for identification of hard dispersions (HD) and their differences from physical mixtures (PM) by benzene PEG-4000 model systems. A complex of physiocochemical methods showed that benzonal and PEG-4000 are not thermally destroyed during simultaneous melting at 140 degrees C. Differences in thermoanalytical characteristics of PM and HD, expressed in suppression of phase transition temperatures, changes in the type of melting peaks and heats, and in the absence of drug melting peak and heats in HD vs. PM confirm the formation of new physiochemical systems differing from PM. The resultant quantitative relationships between temperature depression and melting heats for HD and PM of different composition correlate with chromatographic findings.
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PMID:[Prospects of using hard dispersions in development of dosage forms for therapeutic and prophylactic use]. 1125 53

The toxicity of benzene, a chemical used in many industrial processes, involves bone marrow depression and leukemogenesis and is associated with damage to multiple classes of hematopoietic cells and hematopoietic functions. Environmental exposure to benzene causes an increased body burden, which is reflected in several biomarkers, eg, urine trans,trans-muconic acid (ttMA). Associated with the industrialization of Thailand, a developing country in Southeast Asia, workers in many occupations have acquired substantial risks of benzene exposure. In this study, benzene exposure was monitored by high-performance liquid chromatography (HPLC) of urine ttMA in 79 persons, including 49 controls and 30 gas station attendants. In controls, urine ttMA concentration averaged 0.12 (SD +/- 0.03) mg/g creatinine; in gas station attendants, urine ttMA concentration averaged 4.00 (SD +/- 12.49) mg/g creatinine (p < 0.05). Based on these findings, wider use of urine ttMA determination is recommended as a biomarker for occupational exposure to benzene.
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PMID:Urine trans,trans-muconic acid as a biomarker for benzene exposure in gas station attendants in Bangkok, Thailand. 1168 52

Estrogen receptor (ER) activity can be modulated by the action of other nuclear receptors. To study whether ER activity is altered by orphan nuclear receptors that mediate the cellular response to xenobiotics, cross-talk between ER and constitutive androstane receptor (CAR), steroid and xenobiotic receptor, or peroxisome proliferator-activated receptor gamma was examined in HepG2 cells. Of these receptors, CAR substantially inhibited ER-mediated transcriptional activity of the vitellogenin B1 promoter as well as a synthetic estrogen responsive element (ERE)-containing promoter. Treatment with an agonist of CAR, 1,4-bis-(2-(3,5-dichloropyridoxyl))benzene, potentiated CAR-mediated transcriptional repression. In contrast, an antagonist of CAR, androstenol, alleviated the repression effect. Although CAR interacted with the ER in solution, CAR did not interact with the ER bound to the ERE. CAR/retinoid X receptor bound to the ERE but with much lower affinity than ER. Incremental amounts of CAR elicited a progressive reduction of the ER activity induced by the p160 coactivator glucocorticoid receptor interacting protein 1 (GRIP-1). In turn, increasing amounts of GRIP-1 progressively reversed the depression of ER activity by CAR. An agonist or antagonist of CAR potentiated or alleviated, respectively, the CAR-mediated repression of the GRIP-1-enhanced ER activity, which is consistent with the ability of theses ligands to increase or decrease, respectively, the interaction of CAR with GRIP-1. A CAR mutant that did not interact with GRIP-1 did not inhibit ER-mediated transactivation. Our data demonstrate that xenobiotic nuclear receptor CAR antagonizes ER-mediated transcriptional activity by squelching limiting amounts of p160 coactivator and imply that xenobiotics may influence ER function of female reproductive physiology, cell differentiation, tumorigenesis, and lipid metabolism.
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PMID:Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators. 1211 25


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