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PubMed1996

[Acute appendicitis caused by mucorales in a patient with severe aplastic anemia: report of an autopsy case].

A male patient with severe aplastic anemia was admitted for bone marrow transplantation. While waiting for a donor, high doses of methylprednisolone, anabolic steroid and granulocyte colony stimulating factor were given without response. Deferoxamine was administered for prophylaxis of hemochromatosis because of high level of ferritin. Acute right lower abdominal pain and pyrexia developed. A diagnosis of acute appendicitis was made and appendectomy was performed. The histopathological examination of the resected appendix revealed necrotizing hemorrhagic appendicitis with numerous hyphae of Mucorales. Though anti-fungal agent (amphotericin B) administration was continued, he subsequently developed ileo-cecal abscess and eventually died due to myoglobinuric nephropathy caused by extensive necrosis of the iliopsoas muscle. Autopsy revealed dissemination of hyphae of Mucorales in lungs, kidneys, large vessels and muscle of the bilateral lower limbs. Systemic vascular invasion and embolization of fungal hyphae were also observed. However, culture of exudate sampled from ileocecum yielded no Mucorales. It was emphasized that antemortem diagnosis and effective anti-fungal treatments are essential for the management of intestinal mucormycosis. The relation ship between mucormyocosis and deferoxamine was also discussed.

Acute Disease↗

PubMed1996

Class III antiarrhythmic effects of ceruloplasmin on rat heart.

Recently it has been shown that ceruloplasmin presents a protective action against reperfusion-induced arrhythmias in the isolated perfused rat heart, an effect that is lost when the protein is denaturated by heat. The present study was carried out to see whether ceruloplasmin can alter electrophysiological properties such as ventricular effective refractory periods, conduction time, and action potential duration calculated at 50, 75, and 90% levels of repolarization (APD50, APD75, APD90). To check the specificity of the electrophysiological effects of ceruloplasmin, we have also compared them with those of heat-denatured ceruloplasmin, superoxide dismutase, catalase, deferoxamine, and albumin. In isolated rat hearts, ceruloplasmin (0.25-3 microM) (n = 8 for each concentration) was shown to increase the effective refractory period in a concentration-dependent manner by 26 to 89%. Conduction time was not significantly altered. Heat-denatured ceruloplasmin (0.50-3 microM) (n = 8 for each concentration) increased the effective refractory period by 33 to 70% and did not affect the conduction time. In contrast, superoxide dismutase (1-4 microM), catalase (1-2 microM), deferoxamine (500 microM-1 mM), and albumin (1-4 microM) (n = 8 for each substance and for each concentration) had no significant effect on effective refractory period and conduction time at any dose, suggesting that the ceruloplasmin effect might be specific. In rat ventricular preparations, ceruloplasmin (1 microM) also induced a constant prolongation of APD50 (52%), APD75 (64%), and APD90 (41%) after 15 min of infusion (n = 6). The prolongation of effective refractory period and of action potential duration, by native and heat-denatured ceruloplasmin, suggests that this substance has specific class III effects, although this cannot entirely account for its antifibrillatory action at reperfusion in isolated rat hearts.

Action Potentials↗

PubMed1997

Inhibition by hydroxyl radicals of calcitonin gene-related peptide-mediated neurogenic vasorelaxation in isolated canine lingual artery.

Canine lingual arteries are innervated by calcitonin gene-related peptide (CGRP)-containing vasodilator nerves. Although the vascular system might be considered as the first target of oxygen-derived free radicals in some of the pathophysiological conditions, the effect of oxygen-derived free radicals on neurotransmission in CGRP nerves remains unknown. We, therefore, investigated the role of oxygen-derived free radicals generated from Fenton's reagent (3 x 10(-4) M H2O2 plus 2 x 10(-4) M FeSO4) on CGRP-mediated neurogenic relaxation of canine lingual artery ring preparations. In all experiments, endothelium-denuded preparations (which were suspended in the tissue bath for isometric tension recordings) were treated with guanethidine (5 x 10(-6) M) to block neurogenic constrictor responses. The periarterial nerve stimulation (10 V, 4-16 Hz, for 45 sec), exogenous CGRP (10(-8) M) or the ATP-sensitive K+ channel opener cromakalim (10(-6) M) produced relaxation of the rings at a stable plateau tension by the addition of norepinephrine (10(-5) M); the relaxations elicited by CGRP and cromakalim were human CGRP-(8-37)- and glibenclamide-abolishable, respectively. When the nerve stimulation, CGRP and cromakalim were given after H2O2/FeSO4 exposure (Fenton's reagent was removed from the tissue bath), the observed relaxations were markedly diminished. The effects afforded by the early exposure to H2O2/FeSO4 reaction of the preparations were significantly protected by catalase (100 U/ml, H2O2 scavenger), dimethylthiourea (1 mM, H2O2 and HO. scavenger), dimethyl sulfoxide (100 mM, HO. scavenger), deferoxamine (1 mM, a powerful iron chelator) and by a cocktail of catalase-deferoxamine. Generation of HO. from H2O2/FeSO4 was studied by electron spin resonance spectroscopy using the spintrap 5,5-dimethyl-1-pyrroline-N-oxide. We found that H2O2/ FeSO4 reaction formed a 1:2:2:1 quartet, characteristic of the HO-5,5-dimethyl-1-pyrroline-N-oxide spin adduct. After exposure to capsaicin (10(-5) M) or H2O2/FeSO4 of the artery ring preparations, the intensity of CGRP-like immunoreactivity of the periarterial nerves was reduced drastically; the relaxation caused by the nerve stimulation was nearly fully inhibited by capsaicin and H2O2/FeSO4 reaction. The relaxant response, however, to nitroglycerin (10(-5) M) in the presence of norepinephrine to induce tone was unaffected by the early H2O2/ FeSO4 exposure. The data obtained from the present study indicate that HO., rather than H2O2, is the active agent in CGRP-mediated neurogenic relaxation. It is suggested that the HO. can deplete endogenous CGRP localized prejunctionally and also damage CGRP-induced relaxation of canine lingual artery preparations that is caused by activation of ATP-sensitive K+ channels at postjunctional sites. It is also postulated that the second messenger system of the relaxation mediated, at least, by cyclic GMP may be less susceptible to HO..

Animals↗

PubMed1996

Inhibition of Trypanosoma cruzi epimastigotes in vitro by iron chelating agents.

The relative effectiveness of 20 iron chelating agents in suppressing the growth and multiplication of Trypanosoma cruzi epimastigotes has been examined in vitro. 1,2-Dimethyl-3-hydroxypyrid-4-one (L1) and several of its newly synthesised N-substituted analogs containing hydrophobic substituents were significantly more effective than deferoxamine, even though they possess only two donor sites for iron(III) while deferoxamine has six. Analogs with hydrophilic substituents were uniformly less active than L1 itself. Variations in effectiveness as the polarity of the compound is varied indicate that the ability to cross the cellular membrane is of critical importance in the determination of the in vitro trypanocidal activity of iron(III) chelating agents. A group of four tris(2-aminoethyl)amine based tris-imines were also screened, all of which had poor activity (0-28% inhibition). Among the other iron(III) chelating agents which showed a relatively high level of activity at 50 and 100 micrograms/ml were salicylhydroxamic acid (70 and 73% inhibition) and hydroxyurea (42 and 52% inhibition). N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and acetohydroxamic acid exhibited only slight activity at 50 and 100 micrograms/ml. The best of these iron(III) chelating agents were as effective against the epimastigote form at both 50 and 100 micrograms/ml (74-82% inhibition) as benznidazole (81% inhibition), the drug currently used in the clinic.

Animals↗

PubMed1997

Protection from gentamicin ototoxicity by iron chelators in guinea pig in vivo.

This study details the prevention of gentamicin-induced hearing loss in guinea pig in vivo. The approach is based on our recent demonstrations of a redox-active gentamicin-iron complex in vitro and partial attenuation of gentamicin-induced hearing loss by the iron chelators deferoxamine and 2,3-dihydroxybenzoate. In our study, guinea pigs receiving injections of gentamicin (120 mg/kg body weight daily x 19 days) developed a progressive threshold shift reaching 50 to 70 dB at 18 kHz. Concurrent treatment with different doses of 2,3-dihydroxybenzoate (30-300 mg/kg/day) reduced the threshold shift to 25 to 15 dB. Coinjection of gentamicin with dihydroxybenzoate (100 mg/kg/day) plus mannitol (15 mg/kg/day) yielded complete functional and morphological protection from gentamicin ototoxicity although partial protection was observed with combinations of dihydroxybenzoate and deferoxamine. Dihydroxybenzoate also attenuated gentamicin-induced vestibular toxicity. The iron chelators and radical scavengers affected neither serum levels nor the antimicrobial efficacy of gentamicin against Escherichia coli. These results confirm that iron and free radicals play a crucial role in the toxic side effects of gentamicin. Furthermore, they suggest that iron chelators, which are well-established drugs in clinical therapy, may be promising therapeutic agents to reduce aminoglycoside ototoxicity.

Animals↗

PubMed1998

A fatal case of acute ferric chloride poisoning.

Death from ferric chloride poisoning has never been reported in Taiwan. We report a fatality from the suicidal ingestion of ferric chloride solution used as an etching agent for printed circuitry. A 25-y-old woman presented with vomiting after ingestion of 200 ml ferric chloride solution (pH 1.0). She had hypoxemia and severe metabolic acidosis with respiratory alkalosis initially. Three hours after her ingestion she presented with drowsy consciousness, tachycardia, tachypnea and protracted vomiting. Laboratory studies showed leukocytosis, elevated glucose, aspartate aminotransferase, amylase, lactate dehydrogenase, and total bilirubin, coagulation defect and hemolysis. Aspiration pneumonia and vision loss were also noted. Four hours after ingestion cardiopulmonary arrest suddenly occurred after severe vomiting and she expired. Toxicological studies showed marked elevation of serum iron (2440 micrograms/dl); the estimated oral dose of ferric chloride was equivalent to 11.52 g (230 mg/kg) of elemental iron. This patient did not receive deferoxamine due to rapid deterioration and a late diagnosis. Deferoxamine should be given in any symptomatic patient or in the presence of anion gap metabolic acidosis with a history of ferric chloride ingestion.

Acidosis↗

PubMed1998

Rebamipide protects against oxygen radical-mediated gastric mucosal injury in rats.

Rebamipide, a novel antiulcer agent, has been shown to protect against gastric injury by free radicals. The effect of rebamipide was examined using two rat models of mucosal injury: the stomach was exposed to luminal perfusion of 10 mM H2O2 for 10 min or to local ischemia for 30 min. The effect of deferoxamine, a chelator of Fe3+, was also evaluated to determine whether Fe3+-mediated production of hydroxyl radicals contributed to the damage induced by H2O2. The pylorus was ligated and a double-lumen cannula was inserted into the forestomach for luminal perfusion. [51Cr]EDTA was administered intravenously and mucosal integrity was monitored by measuring blood-to-lumen [51Cr]EDTA clearance. Rebamipide reduced the increase in EDTA clearance induced by ischemia or H2O2. Furthermore, deferoxamine attenuated the H2O2-induced increase. These results suggest that rebamipide has a protective effect against oxygen radical-mediated gastric damage and that Fe3+ is involved in the H2O2-induced injury.

Alanine↗

PubMed2003

Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruch's membrane.

OBJECTIVE: To investigate whether iron is involved in the pathogenesis of age-related macular degeneration (AMD). METHODS: Postmortem AMD-affected (nonexudative or exudative) and healthy maculas were studied using the 3,3'-diaminobenzidine-enhanced Perls Prussian blue stain. The Perls Prussian blue stain was quantified by computer-assisted analysis of digital images. To determine whether the iron was chelatable, sections treated with the iron chelator deferoxamine were compared with adjacent, nonchelated sections. RESULTS: Compared with healthy maculas, AMD-affected maculas had statistically significant increases in the total iron level. Some of this iron was chelatable. The iron was present in retinal pigment epithelium and Bruch's membrane in maculas from patients who had drusen only, geographic atrophy, and exudative AMD in pathologic areas and, occasionally, in relatively healthy areas. CONCLUSIONS: Oxidative stress has been implicated in the pathogenesis of AMD by the Age-Related Eye Disease Study. Increased concentrations of iron, which generate highly reactive hydroxyl radicals via the Fenton reaction, may induce oxidative stress in the macula and lead to AMD. As the increased iron concentrations in AMD-affected eyes consist in part of a chelatable iron pool, treatment of patients who have AMD with iron chelators might be considered a potential therapy. While there are, as yet, no clinical data indicating that the treatment of patients who have AMD with iron chelators is beneficial, data presented herein indicate that further investigation of iron concentrations in postmortem tissues and the mechanisms of iron transport in the retina is warranted.

3,3'-Diaminobenzidine↗

PubMed1988

A prospective evaluation of iron chelation therapy in children with severe beta-thalassemia. A six-year study.

Sixteen patients (age range, 3 to 17 years) with transfusion-dependent beta-thalassemia major were studied prospectively, beginning at the onset of chelation therapy with deferoxamine (desferrioxamine). A liver biopsy specimen was obtained from each patient at the start of the study, and periodically thereafter. Liver histologic features, iron content, and iron excretion were assessed during the course of the study. Hepatic iron levels from liver biopsy specimens appeared to correlate well with serum ferritin levels in the younger less heavily iron-loaded patients; however, in patients with higher serum ferritin levels, hepatic iron appeared to reach a saturation level. Fourteen of the 16 patients showed a pattern of marbled fibrosis of the liver in their initial biopsy specimens. Follow-up biopsy specimens from nearly all of the patients showed a substantial reduction in iron concentration, but only two of seven patients showed improvement in the degree of hepatic fibrosis three to five years later. Patients less than 8 years old exhibited a normal pattern of linear growth until approximately the age of 10 years, followed by a progressive decrease to the 30th to 40th percentile. Two patients, aged 18 and 22 years, died of cardiac disease during the study. These findings suggest that chelation therapy in patients with transfusion-dependent thalassemia needs to be initiated at an early age, possibly before 3 years, if significant liver fibrosis and growth impairment are to be effectively prevented.

Adolescent↗

PubMed1994

Prognostic significance of left ventricular diastolic indexes in beta-thalassemia major.

OBJECTIVE: To define the prognostic significance of left ventricular diastolic function in patients with beta-thalassemia major by noninvasive M-mode echocardiography and Doppler measurements. DESIGN: Cohort analytic study. SETTING: A university hospital in Taipei, Taiwan. PATIENTS: Forty-five patients (age range, 4 to 25 years) with transfusion-dependent beta-thalassemia major followed up for 5 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: M-mode and Doppler echocardiography were used to determine the left systolic time interval; ejection fraction; left atrium emptying index; isovolumetric relaxation period; diastolic total period; the duration, slope, and height of the early diastolic flow-velocity peak; and the ratio between the heights of early and atrial diastolic flow-velocity peaks. All patients had normal systolic ventricular function initially, but impaired diastolic function developed, especially in the older age group who had more evidence of iron loading. In nine of those with abnormal diastolic total period (n = 10) and duration of the early diastolic flow-velocity peak (n = 12) values, regardless of age, congestive heart failure developed during the period of follow-up. Of these nine, four died within 2 years after the advent of heart failure and five remained compensated after anticongestive treatment and use of deferoxamine mesylate. The presence of an abnormal diastolic total period and duration of the early diastolic flow-velocity peak values correlated well with the prognosis. CONCLUSIONS: Left ventricular diastolic filling variables by echocardiography are important predictors of the outcome of patients with transfusion-dependent beta-thalassemia major and could provide useful measures in determining the effects of medication during long-term follow-up.

Adolescent↗

PubMed1988

Hydrogen peroxide-mediated inhibition of T-cell response to mitogens is a result of direct action on T cells.

Hydrogen peroxide, a reactive oxygen intermediate produced by activated neutrophils, has been shown to inhibit the response of human T lymphocytes to mitogens and alloantigens. Since hydrogen peroxide is known to react with iron and to induce lipid peroxidation, we compared the effects of hydrogen peroxide and a lipid peroxidation product, malondialdehyde, on the response of human peripheral blood mononuclear cells to T-cell mitogens. Peripheral blood mononuclear cells pretreated with 1 mmol/L of malondialdehyde, washed, and resuspended in fresh medium exhibited no inhibition of phytohemagglutinin responsiveness. Peripheral blood mononuclear cells treated in the same manner but with 200 mumol/L of hydrogen peroxide were inhibited by more than 95%. The addition of ferric edetate did not alter the inhibitory effects of 50 to 100 mumol/L of hydrogen peroxide, nor did the addition of deferoxamine, an iron chelator. These studies suggest that exogenous lipid peroxidation does not affect lymphocyte activation but that hydrogen peroxide has a direct inhibitory effect. Although monocytes are necessary for T-cell mitogenic responses, the effect of hydrogen peroxide was found to be directed at T lymphocytes. Exposure of T cells to a single dose of 200 mumol/L of hydrogen peroxide resulted in more than 71% suppression of the proliferative response measured 48 hours later, but the effect was spontaneously reversed by 72 to 96 hours. Repeated exposure of the cells to hydrogen peroxide resulted in continued inhibition of the proliferative response. These findings suggest that hydrogen peroxide produced by inflammatory phagocytic cells might be capable of suppressing the immune response of nearby T lymphocytes.

Deferoxamine↗

PubMed1995

Suppressors of oxygen metabolites fail to reduce vein graft intimal hyperplasia.

OBJECTIVE: To evaluate the role of reactive oxygen metabolites in the initiation of intimal hyperplasia of vein grafts inserted into the arterial circulation. SETTING: University pathologic research laboratory. ANIMALS: Sprague-Dawley rats. INTERVENTION: Animals were randomized to receive either the xanthine oxidase inhibitor allopurinol, the iron chelating agent starch-conjugated deferoxamine, or the free-radical scavenger 21-aminosteroid U74389G. Control animals were included for each group. The epigastric vein was inserted into the right common femoral artery. Vein grafts were harvested 30 days postoperatively. The degree of intimal hyperplasia at the two anastomoses as well as at the midgraft was calculated. MAIN OUTCOME MEASURES: The vein grafts were divided into three sections designated proximal anastomosis, midgraft, and distal anastomosis. Intimal and medial areas were determined in an observer-blind fashion and expressed as intimal area-medial area ratios. RESULTS: Pretreatment of the animals with any of these agents resulted in no significant reduction in the degree of intimal hyperplasia in any treated groups compared with the control animals 30 days postoperatively. CONCLUSIONS: Arterial reconstruction often involves interposition of vein segments into the arterial circulation. These veins are subject to ischemia and reperfusion, with the potential for generation of reactive oxygen metabolites and subsequent vein graft injury, resulting in intimal hyperplasia. We hypothesized that perioperative pharmacologic intervention either to scavenge or to reduce the production of reactive oxygen metabolites would attenuate the initial vein graft injury and thus limit the subsequent development of intimal hyperplasia. These data create doubt as to the influence of reactive oxygen metabolites in the initiation of intimal hyperplasia in the vein graft.

Allopurinol↗

PubMed1996

Aluminum toxicity following intravesical alum irrigation for hemorrhagic cystitis.

Mental status changes in an immunosuppressed child can be due to a variety of causes; aluminum toxicity is rarely considered. We report a teenage girl with acute lymphoblastic leukemia who developed mental status changes, speech disturbance, coarse tremor, and abnormal EEG findings following intravesical 1% alum irrigation and administration of aluminum-containing antacids. Her serum aluminum levels were mildly elevated (14-22 milligram(s), normal 0-6 milligram(s)), and bone marrow biopsy specimens demonstrated aluminum deposition on special staining (Krueger's method). All abnormalities resolved after a nine-week course of intravenous deferoxamine.

Adolescent↗

PubMed1999

Sodium selenite-induced oxidative stress and apoptosis in human hepatoma HepG2 cells.

The mechanisms involved in the anti-carcinogenic activity of selenium remain to be elucidated. In the present study, we examined sodium selenite-induced oxidative stress and apoptosis in a human hepatoma cell line (HepG2). Sodium selenite (10 microM) exerted clear cytotoxic effect, as shown by the significant increase of lactate dehydrogenase leakage. Selenite-induced DNA alterations in apoptosis were studied by: 1. comet assay; 2. TdT-mediated dUTP nick end-labeling assay. In addition, characteristic apoptotic morphological alterations were also observed in selenite-treated cells. Our results clearly show that Se-induced cell death occurs predominantly in the form of apoptosis. Selenite-induced oxidative stress was evaluated by the measurement of reactive oxygen species production using lucigenin-dependent chemiluminescence. The involvement of glutathione in selenite-induced oxidative stress was further demonstrated by the concurrent decline of intracellular reduced glutathione and increase of oxidized glutathione contents in Se-treated cells. Moreover, the finding that selenite-induced oxidative stress and apoptosis was significantly attenuated by superoxide dismutase, catalase and deferoxamine provides additional evidence to suggest that Se-induced oxidative stress mediates the induction of apoptosis, a mechanism related to the anti-carcinogenic and chemopreventive effect of Se.

Apoptosis↗

PubMed1998

Increase of reactive oxygen species (ROS) in endothelial cells by shear flow and involvement of ROS in shear-induced c-fos expression.

Intracellular reactive oxygen species (ROS) may participate in cellular responses to various stimuli including hemodynamic forces and act as signal transduction messengers. Human umbilical vein endothelial cells (ECs) were subjected to laminar shear flow with shear stress of 15, 25, or 40 dynes/cm2 in a parallel plate flow chamber to demonstrate the potential role of ROS in shear-induced cellular response. The use of 2',7'-dichlorofluorescin diacetate (DCFH-DA) to measure ROS levels in ECs indicated that shear flow for 15 minutes resulted in a 0.5- to 1.5-fold increase in intracellular ROS. The levels remained elevated under shear flow conditions for 2 hours when compared to unsheared controls. The shear-induced elevation of ROS was blocked by either antioxidant N-acetyl-cysteine (NAC) or catalase. An iron chelator, deferoxamine mesylate, also significantly reduced the ROS elevation. A similar inhibitory effect was seen with a hydroxyl radical (.OH) scavenger, 1,3-dimethyl-2-thiourea (DMTU), suggesting that hydrogen peroxide (H202), .OH, and possibly other ROS molecules in ECs were modulated by shear flow. Concomitantly, a 1.3-fold increase of decomposition of exogenously added H2O2 was observed in extracts from ECs sheared for 60 minutes. This antioxidant activity, abolished by a catalase inhibitor (3-amino-1,2,4-triazole), was primarily due to the catalase. The effect of ROS on intracellular events was examined in c-fos gene expression which was previously shown to be shear inducible. Decreasing ROS levels by antioxidant (NAC or catalase) significantly reduced the induction of c-fos expression in sheared ECs. We demonstrate for the first time that shear force can modulate intracellular ROS levels and antioxidant activity in ECs. Furthermore, the ROS generation is involved in mediating shear-induced c-fos expression. Our study illustrates the importance of ROS in the response and adaptation of ECs to shear flow.

Acetylcysteine↗

PubMed2001

Variations of ferritin levels over a period of 15 years as a compliance chelation index in thalassemic patients.

We studied the changing pattern of the distribution of ferritin levels in 430 regularly-transfused patients with thalassemia in an attempt to evaluate compliance of chelation with deferoxamine. The study covered 15 years and was divided in three periods: 1981-1985, 1986-1990, and 1991-1995. The patients were stratified in age-groups. The mean ferritin levels of each period were calculated for each patient individually. The study showed that: (i) When all the patients were compared as a group, there was a significant decrease in mean ferritin between 1981-1985 and 1991-1995, despite a significant change in the patients' mean age; (ii) When patients of same age were compared between periods, there was a decrease in mean ferritin between 1981-1985 and 1991-1995, as well as a decrease in the proportion of patients with ferritin >4000 microg/L, with a parallel increase in the proportion of patients who had ferritin <2000 microg/L; (iii) When the same patients were followed longitudinally, they showed a decrease in their ferritin levels in all age groups with the exception of the late adolescence period. The decrease in iron overload observed in patients on close follow up implies that compliance with chelation therapy has improved with time and therefore, a favourable influence in survival could be expected.

Adolescent↗

PubMed2002

Induction of ferritin and lipid peroxidation by coal samples with different prevalence of coal workers' pneumoconiosis: role of iron in the coals.

BACKGROUND: Differences in levels of bioavailable iron (BAI) in coal may be responsible for the observed regional differences in the prevalence and severity of coal workers' pneumoconiosis (CWP). METHODS: Twenty-nine coal samples from three coal mine regions were tested in human lung epithelial Type II A549 cells. They were from Utah (UT), West Virginia (WV), and Pennsylvania (PA) with a prevalence of CWP of 4, 10, and 26%, respectively. RESULTS: Low molecular weight (LMW) chelators bound iron, a fraction of BAI in the cells released from coals, ferritin, and lipid peroxidation were significantly higher in cells treated with various coals than in control cells, with an increasing order of UT < WV < PA, in parallel to the prevalence of CWP in these coal mine regions. Deferoxamine (DFO), a specific iron chelator, was used to distinguish effects of BAI from those of other transition metals. Our results indicate that BAI in the coals of WV and UT is the main metal species in inducing ferritin and lipid peroxidation. In contrast, biological effects of PA coals are not only from BAI, but from other transition metals as well. CONCLUSIONS: Based on a large number of coal samples from various seams, the findings of this study provide further evidence that metals, particularly iron, play important roles in coal dust-induced cellular damage, ultimately leading to the development of CWP and contributing to the regional differences in the prevalence of the disease.

Cells, Cultured↗

PubMed2005

Involvement of oxygen free radicals in the serum-mediated increase of benzoquinone genotoxicity.

The genotoxicity of benzoquinone (BQ), a toxic benzene metabolite, is greatly enhanced by the presence of fetal calf serum (FCS) in the incubation medium. The FCS effect is abolished by heat denaturation of serum proteins and is slightly decreased by dialysis. In the present study, we have further investigated the serum effect on BQ genotoxicity by measuring DNA damage produced in peripheral blood mononuclear cells (PBMCs) using the Comet assay. We have also evaluated the effect of human serum and rat liver post-mitochondrial fraction (S9) on the DNA damage produced by BQ. Both human serum and a rat liver S9 enhanced the genotoxicity of BQ in a manner similar to FCS. Gel filtration experiments showed that all the enhancing activity of the serum eluted with the high molecular weight fractions, suggesting that low molecular weight serum constituents do not play an important role in modulating genotoxicity. The genotoxicity-enhancing activity of serum was inhibited by the iron chelator deferoxamine and by superoxide dismutase and catalase. Incubating PBMCs with BQ in the presence of FCS also resulted in the accumulation of intracellular peroxides as demonstrated by loading the cells with 2',7'-dichlorofluorescin diacetate and analyzing for peroxide formation by flow cytometry. These results indicate that oxygen free radicals are involved in the enhancement of BQ-induced DNA damage by serum. We hypothesize that enzyme activities that reduce BQ by transferring single electrons could be the source of the oxygen free radicals.

Animals↗