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PubMed1987

Kinetic studies on benzene metabolism in rat liver--possible presence of three forms of benzene metabolizing enzymes in the liver.

The effects of food deprivation, ethanol consumption and phenobarbital (PB) administration on in vitro benzene metabolism in rat liver were studied by using benzene concentration ranging from 0.0055 to 6.25 mM. The kinetic analysis suggested that the liver of normally-fed rats contained two forms of benzene hydroxylases each with a Km value of 0.01 mM or 0.07 mM. The isozyme with a Km of 0.01 mM disappeared following one-day food deprivation, but the deprivation enhanced the activity of the other isozyme. Ethanol treatment markedly increased the activity of both normally-existing enzymes. On the other hand, PB treatment induced the synthesis of another benzene-metabolizing enzyme with a high Km value of 4.5 mM, the presence of which was indistinct in normal rats. The treatment had no influence on the activity of either of the normally-occurring low-Km isozymes. The combined effects of PB with food deprivation were additive, suggesting that the induction of low- and high-Km isozymes is each independent of the other.

Alcohol Drinking↗
PubMed1981

Relationship between benzene toxicity and the disposition of 14C-labelled benzene metabolites in the rat.

The distribution of radioactivity associated with three 14C-labelled benzene metabolites was studied using whole body autoradiography (WBAR). Male Fischer-344 rats were given an intravenous dose of 0.6 mg/kg (60 microCi phenol, 1.2 mg/kg (100 microCi) catechol, or 1.3 mg/kg (100 microCi) hydroquinone. The rats were killed after 2 h and autoradiograms were prepared from whole body sagittal sections. The relative organ uptake of radioactivity associated with each compound was assessed by comparing tissue/blood optical density (O.D.) ratios from X-ray films. Bone marrow, thymus and the white pulp of the spleen concentrated radioactivity associated with hydroquinone or catechol. Radioactivity associated with phenol concentrated in the red pulp of the spleen, but not in the other lymphoid tissues. Radioactivity associated with all three metabolites was found in the lungs, kidneys and small intestines, whereas greater accumulation of radioactivity was observed in subcutaneous tissues, sebaceous glands and the white matter of the brain and spinal cord in rats given hydroquinone or catechol than in animals given phenol. Rats pretreated with a single dose of Aroclor 1254 (250 mg/kg, i.p.), a regimen which was found to protect against benzene-induced lymphocytopenia, were given hydroquinone (100 microCi; 1.3 mg/kg) or catechol (100 microCi; 1.4 mg/kg). For hydroquinone the tissue/blood O.D. ratios for bone marrow and thymus were approx. 60% lower in Aroclor-pretreated than in untreated rats. A 25% reduction in the tissue/blood O.D. ratios for these organs was observed in pretreated rats given catechol. These findings indicate that the uptake and concentration of radioactivity associated with hydroquinone and catechol by bone marrow and lymphoid organs (1) can occur independently of the metabolism of benzene in these tissues and (2) is reduced under conditions in which the animal is less susceptible to benzene toxicity.

Animals↗
PubMed1991

Effects of benzene on DNA strand breaks in vivo versus benzene metabolite-induced DNA strand breaks in vitro in mouse bone marrow cells.

Previously, we identified p-benzoquinone (BQ) and 1,2,4-benzenetriol (BT) as toxic metabolites of benzene on the basis of their inhibitory effect on DNA synthesis. In the present study, the capability of benzene and the two metabolites to induce DNA strand breaks was investigated in either the in vivo or the in vitro system by comparing the DNA elution rate on a fine membrane filter at alkaline pH. In the in vitro system were bone marrow cells were reacted with test chemicals for 60 min, both BQ and BT induced a dose-related increase in alkali-labile DNA single-strand breaks (SSBs) of bone marrow cells. However, when glutathione (350 micrograms/ml) was added to the same reaction system, the DNA damaging effect of BQ (24 microM) and BT (24 microM) was blocked by 100 and 53%, respectively. Catalase (130 units/ml) completely blocked the DNA damaging effect of BT, while no protection was afforded with BQ. Consistent with these observations, no induction of alkali-labile DNA SSBs was observed in the in vivo system by an anesthetic dose of benzene (1760 mg/kg, ip or po) at 1, 24, and 36 hr postadministration in both male and female ICR mice. These results suggest that benzene exposure would not induce direct DNA strand breaks in vivo under realistic work-related or accidental exposure conditions and also indicate that caution should be exercised in the interpretation of in vitro data for whole-body toxicity evaluation.

Animals↗
PubMed1991

Mechanisms of benzene carcinogenesis: application of a physiological model of benzene pharmacokinetics and metabolism.

A physiological pharmacokinetic model for benzene, incorporating metabolic transformations, is used to explore why benzene, but not phenol--its primary metabolite--is carcinogenic at many sites in rats. The model has been parametrized using in vitro or in vivo experimental data. Ranges, rather than fixed values, were assigned to the parameters. The model-predicted levels of phenol and hydroquinone in the tissues are consistently higher when phenol, rather than benzene, is administered. This result demonstrates that the differential carcinogenicity of the two compounds is not explainable in the context of this pharmacokinetic analysis. It also indicates that the phenol-hydroquinone pathway alone is unlikely to account for the carcinogenic effects of benzene. Other metabolites must therefore also be involved.

Administration, Inhalation↗
PubMed1999

Investigation of benzene oxide in bone marrow and other tissues of F344 rats following metabolism of benzene in vitro and in vivo.

This study examines the initial activation of benzene, exploring key aspects of its metabolism by measurement of benzene oxide (BO) and BO-protein adducts in vitro and in vivo. To assess the potential influence of various factors on the production of BO, microsomes were prepared from tissues that were either targets of benzene toxicity, i.e. the bone marrow and Zymbal glands, or not targets, i.e. liver and kidneys, of control and acetone-treated F344 rats. No BO or phenol was detected in microsomal preparations of bone marrow or Zymbal glands (less than 0.007 nmol BO/mg protein and 0.7 nmol phenol/mg protein). On the other hand, BO and phenol were readily detected in preparations of liver and kidney microsomes and acetone pretreatment resulted in a 2-fold (kidney) increase or 3.7-fold (liver) increase in production of these metabolites. Initial rates of BO production in the liver isolates were 30 (control) to 50 (acetone-treated) times higher than in the corresponding kidney tissues. The estimated half-life of BO in bone marrow homogenates was 6.0 min and the second-order reaction rate constant was estimated to be 1.35 x 10(-3) l (g bone marrow)(-1) (h)(-1). These kinetic constants were used with measurements of BO-bone marrow adducts in F344 rats, receiving a single gavage dosage of 50-400 mg benzene (kg body weight)(-1) (McDonald, T.M., et al. (1994), Cancer Res. 54, 4907-4914), to predict the bone marrow dose of BO. Among the rats receiving 400 mg (kg body weight) (-1), a BO dose of 1.13 x 10(3) nM BO-h was estimated for the bone marrow, or roughly 40% of the corresponding blood dose predicted from BO-albumin adducts. Together these data suggest that, although BO is not produced at detectable levels in the bone marrow or Zymbal glands of F344 rats, BO is rapidly distributed via the bloodstream to these tissues where it may play a role in toxicity.

Animals↗
PubMed1988

Inhibition of interferon gamma production by benzene and benzene metabolites.

We exposed spleen cells from female Swiss/Webster mice to benzene and benzene metabolites to determine the effects of such exposure on interferon gamma induction by concanavalin A. Exposing the cells to benzene or phenol did not affect interferon gamma production, but exposing them to p-benzoquinone, catechol, or hydroquinone significantly inhibited interferon gamma production. Cell viability, as determined by trypan blue viability staining, was not influenced by the chemical treatment. When interferon gamma production was inhibited, the inhibition was dose dependent. The time of optimum production of interferon gamma after exposure to concanavalin A was not affected by treatment of the cells with p-benzoquinone. These data indicate the importance of dihydroxy and diketo metabolites as immunotoxic derivatives of benzene.

Animals↗
PubMed2006

Causal relationship between non-Hodgkin's lymphoma and exposure to benzene and benzene-containing solvents.

Non-Hodgkin's lymphoma (NHL) is a malignant neoplasm of the lymphatic system made up of mainly B cell lymphocytes. A large number of studies have shown significant associations between NHL and benzene or benzene-containing solvents and products. This article summarizes studies detailing these associations and indicates those that are significant. Based on an analysis of the literature and the weight of evidence from numerous studies, it is reasonable to conclude that exposure to benzene or to solvents or products containing benzene is causally related to NHL.

Benzene↗
PubMed1996

Cell-specific activation and detoxification of benzene metabolites in mouse and human bone marrow: identification of target cells and a potential role for modulation of apoptosis in benzene toxicity.

The role of cell-specific metabolism in benzene toxicity was examined in both murine and human bone marrow. Hemopoietic progenitor cells and stromal cells are important control points for regulation of hemopoiesis. We show that the selective toxicity of hydroquinone at the level of the macrophage in murine bone marrow stroma may be explained by a high peroxidase/nicotanimide adenine dinucleotide phosphate, reduced [NAD(P)H]:quinone oxidoreductase (NQO1) ratio. Peroxidases metabolize hydroquinone to the reactive 1,4-benzoquinone, whereas NQO1 reduces the quinones formed, resulting in detoxification. Peroxidase and NQO1 activity in human stromal cultures vary as a function of time in culture, with peroxidase activity decreasing and NQO1 activity increasing with time. Peroxidase activity and, more specifically, myeloperoxidase, which had previously been considered to be expressed at the promyelocyte level, was detected in murine lineage-negative and human CD34+ progenitor cells. This provides a metabolic mechanism whereby phenolic metabolites of benzene can be bioactivated in progenitor cells, which are considered initial target cells for the development of leukemias. Consequences of a high peroxidase/NQO1 ratio in HL-60 cells were shown to include hydroquinone-induced apoptosis. Hydroquinone can also inhibit proteases known to play a role in induction of apoptosis, suggesting that it may be able to inhibit apoptosis induced by other stimuli. Modulation of apoptosis may lead to aberrant hemopoiesis and neoplastic progression. This enzyme-directed approach has identified target cells of the phenolic metabolites of benzene in bone marrow and provided a metabolic basis for benzene-induced toxicity at the level of the progenitor cell in both murine and human bone marrow.

Animals↗
PubMed1998

Presence of antibodies to heat stress proteins in workers exposed to benzene and in patients with benzene poisoning.

Heat shock or stress proteins (Hsps) are a group of proteins induced by a large number of xenobiotics, many of which are common in the working and living environment. The biological significance of the presence of antibodies against Hsps in humans is presently unknown. In the present study, 112 workers were selected and divided into four groups on the basis of their level of occupational exposure to benzene: a control group, two groups of workers exposed to either low (< 300 mg/m3) or high concentrations of benzene (> 300 mg/m3) and a group of workers who had experienced benzene poisoning. Blood samples from these workers were assayed for the number of peripheral white blood cells, concentration of hemoglobin, activities of serum superoxide dismutase (SOD), lymphocyte DNA damage and finally for the presence of antibodies to different human heat-shock proteins (Hsp27, Hsp60, Hsp71 and Hsp90). Benzene-poisoned workers showed a high incidence of antibodies against Hsp71 (approximately 40%) which was associated with a decrease in white blood cells (3.84+/-1.13 x 10(9)versus 7.68+/-1.84 x 10(9) in controls) and with an increase in activities of serum SOD (138.43+/-23.15 micro/ml) and lymphocyte DNA damage (18.7%). These data suggest that antibodies against Hsps can potentially be useful biomonitors to assess if workers are experiencing or have experienced abnormal xenobiotic-induced stress within their living and working environment.

Adult↗
PubMed2004

Acute toxicity of binary mixture benzene-ethanol and partition coefficient K(ow) of benzene and ethanol.

The study related to partition coefficients between n-octanol and water of compounds in binary mixture benzene-ethanol was carried out. Partition coefficients of benzene and ethanol for different values of molar ratio of benzene in the mixture were determined. Collected results show statistically significant deviations the K(ow) of benzene for some molar ratios (0.2 to 0.6) from values for pure compound. For ethanol, there are no statistically significant deviations from values for pure compound, however there are some trends of changes of K(ow).

Animals↗
PubMed1989

Benzene-derived free radical--a possible mediator of its carcinogenicity. I. Ultrastructural and functional studies on the effect of benzene on human white blood cells and its possible prevention.

The assumption that benzene exerts its leukemogenic action on cell components after being converted to a transient and relatively stable free radical is supported by the in vitro effect of benzene on the ultrastructure of human peripheral blood polymorphonuclear (PMN) cells, lymphocytes and monocytes. The effect was examined with a transmission and scanning electron microscope and was found to affect both the internal and external architecture of PMN cells and monocytes in a dose-dependent manner. No effect was observed on lymphocytes. Benzene did not affect the phagocytic activity of PMN cells or monocytes. Preincubation with 2-aminoethylthiosulfuric acid, a free radical scavenger, prevented the observed effects of benzene.

Benzene↗
PubMed1996

Equilibrium Ion Pair Acidities of Polyhalogenated Benzenes in THF. Extrapolation to Benzene(1).

The equilibrium cesium ion pair acidities of six polyfluorobenzenes at 25 degrees C and six polychlorobenzenes at -20 degrees C were determined in THF. For fluorinated benzenes the additive (negative) effects of fluorine on pK (partial equilibrium factors) are o = 5.2, m = 3.0, and p = 1.4. From these the cesium ion pair pK (per H) of benzene is extrapolated to be 44.8 at 25 degrees C. For chlorobenzenes the additive contributions for o-, m-, and p-chlorine are 4.2, 2.7, and 2.1, respectively. The corresponding pK of benzene is 47.0 at -20 degrees C. Aggregation studies show that in the concentration range 10(-)(3)-10(-)(4) M the cesium salt of 1,2,4,5-tetrachlorobenzene and the cesium and lithium salts of 1,2,4,5-tetrafluorobenzene are monomeric. The pK of benzene on the Li scale is extrapolated to be 39.5.

Journal Article↗
PubMed1977

Benzene-lecithin interaction interaction in lecithin-benzene solutions. Part L Magnetic deuterium relaxation studies.

2D relaxation times of deuterobenzene in lecithin-benzene solutions were measured at 4.4 and 11 MHz with respect to concentration and temperature. At the temperature of the transition from the micellar solution to the gel state the relaxation behaviour was drastically changed. Analysis of the experimental results performed on the basis of familiar relaxation theory shows that there are sites at which benzene interacts with lecithin in the micellar solution as well as in the gel state. The interaction enthalpies and entropies determined for the two benzene species existing in the gel state are--1.3 kcal/mol,--20 eu and--3.1 kcal/mol, --24 eu.

Benzene↗
PubMed2002

Infrared spectra of gas-phase V(+)-(benzene) and V(+)-(benzene)(2) complexes.

The organometallic ions V+-(benzene) and V+-(benzene)2 are produced by laser vaporization in a pulsed nozzle source. They are trapped and mass selected in an ion-trap/time-of-flight mass spectrometer, and their infrared spectra are measured with resonance-enhanced multiphoton photodissociation (IR-REMPD) spectroscopy with a tunable free-electron laser. Vibrational bands in the 600-1800 cm-1 region are characteristic of the benzene molecular moiety perturbed by the metal cation bonding. Experimental data are compared to the IR spectra derived from density functional calculations. Vibrational patterns in V+-(C6H6) indicate that the metal is bound in an eta6 pi-bonding configuration, while V+-(C6H6)2 is a sandwich. Trapped-ion IR-REMPD is a general method to access the vibrational spectroscopy of organometallic ions and their clusters.

Benzene Derivatives↗
PubMed2005

Regioselective haloaromatization of 1,2-bis(ethynyl)benzene via halogen acids and PtCl2. Platinum-catalyzed 6-pi electrocyclization of 1,2-bis(1'-haloethenyl)benzene intermediates.

[reaction: see text] Treatment of 1,2-bis(ethynyl)benzene (1) with aqueous HX (X = Br, I) in hot 3-pentanone (100-105 degrees C, 2 h) afforded 1,2-bis(1'-haloethenyl)benzene species 2-Br and 2-I in 98% and 95% yields, respectively. The hydrochlorination of endiyne 1 failed to proceed at elevated temperature but was implemented efficiently by PtCl2 (5 mol %) in hot 3-pentanone (100 degrees C, 2 h) to give 1,2-bis(1'-chloroethenyl)benzene 2-Cl in 80% yield. In the presence of PtCl2 (5 mol %), these halides 2-Cl,2-Br, and 2-I were subsequently converted to 1-halonaphthalenes 3-Cl, 3-Br, and 3-I in the mother solution via sequential 6-pi electrocyclization and dehalogenation reactions. PtCl2 (5 mol %) also effected direct haloaromatization of endiyne 1 with HX (X = Cl, Br, I) and gave 1-halonaphthalenes 3-Cl, 3-Br, and 3-I in 64-71% yields. This investigation reports the scope and the regioselectivity of haloaromatization of various enediynes catalyzed by PtCl2.

Benzene Derivatives↗
PubMed1997

Dimethyldioxirane converts benzene oxide/oxepin into (Z,Z)-muconaldehyde and sym-oxepin oxide: modeling the metabolism of benzene and its photooxidative degradation.

Oxidation of 7-oxabicyclo[4.1.0]hepta-2,4-diene (benzene oxide)/oxepin with dimethyldioxirane (DMDO) gave mainly (Z,Z)-muconaldehyde, with complete diastereoselectivity. Similarly, 2-methyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (toluene 1,2-epoxide)/2-methyloxepin gave (Z,Z)-1,6-dioxohepta-2,4-diene, while 2,6-dimethyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (1,2-dimethylbenzene 1,2-epoxide)/2,7-dimethyloxepin gave (Z,Z)-2,7-dioxo-3,5-octadiene. By monitoring the DMDO oxidation of benzene oxide/oxepin by 1H NMR spectroscopy, a significant byproduct was identified as 4,8-dioxabicyclo[5.1.0]octa-2,5-diene (sym-oxepin oxide). This observation supports the hypothesis that the route to (Z,Z)-muconaldehyde proceeds from oxepin via 6,8-dioxabicyclo[5.1.0]octa-2,4-diene (oxepin 2,3-oxide), with a minor pathway leading to sym-oxepin oxide. The DMDO oxidations described provide model systems for the cytochrome P450-dependent metabolism of benzene and for the atmospheric photooxidation of benzenoid hydrocarbons.

Aldehydes↗
PubMed1977

Anti-benzene compounds. Conversion of benzene to toluene by methyl donors, in man.

The level of benzene in blood can be efficiently reduced, an its noxious effect neutralized, by the concurrent administration of either of two groups of organic compounds: 1) methyl donors such as choline and betaine; and, 2) cysteine-HCL. Methionine acts as a precursor of cysteine in the body as uell as a methyl donor like choline and betaine. The appearance of toluene in blood was demonstrated after the sequential ingestion of choline plus betaine, benzene. The results are discussed in relation to clinical application in workers chronically exposed to benzene.

Benzene↗