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PubMed1992

Treatment of reperfusion injury in dogs with experimentally induced gastric dilatation-volvulus.

In dogs, gastric dilatation-volvulus (GDV) is characterized by cardiogenic shock, with resulting hypoperfusion. Treatment goals include reperfusion of transiently ischemic tissues, which indicates that reperfusion injury may be a factor in the physiopathogenesis of GDV. Recently, we obtained data that indicate that reperfusion injury may be involved in experimentally induced GDV. Using this GDV model, we evaluated mortality in 24 dogs of 4 equal groups, treated with deferoxamine (an iron chelator), dimethylsulfoxide (a free radical scavenger), a combination of the 2 drugs, or isotonic saline solution. All 6 dogs that were given deferoxamine survived; however, 3 dogs of the dimethylsulfoxide-treated group, 2 dogs of the combination-treated group, and 4 dogs of the saline-treated group died. Results of the study indicate that mortality associated with experimentally induced GDV is reduced by appropriate and timely pharmacologic intervention to prevent or attenuate reperfusion injury, and that deferoxamine may be more effective than dimethylsulfoxide.

Animals↗
PubMed2003

Therapeutic angiogenesis for patients with limb ischemia by utilization of fibrin meshwork. Pilot randomized controlled study.

AIM: The aim of this paper is to assess the feasibility and efficacy of fibrin in inducing neovascularization as an angiogenic substance and/or carrier for vascular endothelial growth factor (VEGF) in patients with limb ischemia. METHODS: Twenty-three patients with limb ischemia and referred for below the knee amputations were randomized for treatment: group 1, 7 patients received only a saline injection; group 2, 9 received intramuscular injection of fibrin and group 3, 7 received the fibrin composition with deferoxamine and added VEGF(165). The fibrin meshwork was introduced into the popliteal area of the diseased limbs using a dual syringe system (1 contained thrombin solution [1 mg, 5000 U] and 1 contained fibrinogen [1 mg, Baxter Hyland Immuno] solution). In group 3, Deferoxamine (100 microg) and 500 microg of VEGF(165) were added to the fibrinogen solution. RESULTS: In the control group 5 patients had undergone below the knee amputation at the 3-6 month follow-up. Only 1 patient from Group 2 had below the knee amputation 5 months following Fibrin only administration. Clinical improvement was noted in all 8 patients following fibrin administration and in all 7 patients injected with the fibrin meshwork, deferoxamine and VEGF combination. CONCLUSION: IM injection of fibrin is safe and appears to be an efficient method to treat limb ischemia. These findings indicate that use of fibrin may be a novel and simple method for inducing therapeutic angiogenesis.

Adult↗
PubMed1990

The effects of an iron chelator on cellular injury induced by vascular stasis caused by hypothermia.

Rewarming of a cooled rabbit leg was associated with the generation of oxygen-derived free radicals, shown to be instrumental for tissue injury occurring during rewarming. The present study used a compound that, by its ability to bind with free iron, can remove hydroxyl radical (OH.) from tissue. Deferoxamine reduced tissue injury during cooling and rewarming, as evidenced by its ability to decrease tissue release of lactic acid dehydrogenase and creatine kinase. Deferoxamine also reduced the formation of OH. and lipid peroxidation during the rewarming phase. This compound did not have any effect on the arterial blood flow pattern, which uniformly decreased during cooling and was restored during rewarming. The results of this study indicate the efficacy of deferoxamine in reducing cellular injury associated with cold and rewarming and further suggest a role for oxygen-derived free radicals in the pathophysiology of cold-rewarming injury.

Animals↗
PubMed1990

The effect of desferrithiocin, an oral iron chelator, on T-cell function.

Desferrithiocin is a new, potent, orally available iron chelator. To determine whether this drug might be useful not only for iron-overload but also for immunosuppression, we studied the in vitro effects of desferrithiocin on T-lymphocyte function. Like deferoxamine, desferrithiocin inhibited, in a dose-dependent fashion, mitogen- and lectin-induced proliferation of both human and murine T cells. It was active at a concentration of 10 micrograms/mL. The inhibition of proliferation was reversed by ferrous chloride, but not by other metal salts, recombinant IL-2, or conditioned medium. Desferrithiocin also inhibited proliferation of constitutively dividing, and factor-independent EBV-transformed B cell and leukemic T-cell lines. Although desferrithiocin inhibited the induction of cytotoxic T lymphocyte (CTL) activity, it did not inhibit CTL- or natural killer-induced cytotoxicity. The agent did not inhibit the expression of activation antigens such as the IL-2 receptor on T cells, nor early measures of T-cell activation such as the influx of intracellular calcium. Thus, desferrithiocin, like deferoxamine, is a potent and reversible inhibitor of T-cell proliferation. This anti-proliferative effect inhibits T-cell function. Bioavailability after oral administration is a unique property of desferrithiocin, and would make it an attractive alternative to deferoxamine. Its immunomodulating properties may therefore be exploited in vivo to inhibit graft rejection or autoreactive T cells.

Antigens, Surface↗
PubMed1990

Four-hour measurement of urinary iron excretion after deferoxine treatment: a rapid, simple method for study of iron excretion.

In a group of 56 patients being evaluated for iron storage disease, all of whom underwent liver biopsy with quantitative measurement of liver iron concentration, urinary excretion of iron was measured following intramuscular injection of deferoxamine (10 mg/kg body weight). Urine was collected in two portions, 0-4 h and 4-24 h after deferoxamine administration. Iron excretion in the first 4 h was closely correlated to that over the entire 24-h period (r = 0.88, p less than 0.0001, 95% confidence interval = 0.80-0.93), indicating that the 4-h deferoxamine urinary excretion test can be adapted readily to an outpatient clinical setting, helping to insure complete and accurate urine collections. Correlation of 0- to 4-h urinary iron excretion and quantitative liver iron (r = 0.335), although higher than for the full 24 h (r = 0.192), was not sufficient to accurately predict hepatic iron concentration in the individual patient.

Deferoxamine↗
PubMed1988

A study of iron complexation in a swine model.

The treatment of iron poisoning consists of supportive care and efforts to remove or retard the absorption of iron from the gastrointestinal tract. A standard but rarely challenged treatment is to render the unabsorbed iron less soluble by complexing it with bicarbonate or phosphate solution. Another therapy is the use of oral deferoxamine. Bicarbonate and phosphate therapy are known to be associated with adverse outcomes if used inappropriately. Is their use justified? To closely simulate a potentially toxic iron overdose in a 24-month-old child, a swine model was used. Twenty fasted castrated male pigs weighing an average of 14.6 kg (+/- 3.0 kg) were orally dosed with 300 mg/kg FeSO4 (60 mg Fe/kg) and randomly placed into 1 of 4 treatment groups receiving 50 ml of distilled water (control), 5% sodium bicarbonate, 5% sodium dihydrogen phosphate, or deferoxamine (10 g). Sequential serum iron levels were obtained at 0, 1, 2, 4, and 6 hr. There were no significant differences in the absorption of iron, as reflected by serum iron concentrations, in the bicarbonate and phosphate groups when compared to the control group (p greater than 0.05). Deferoxamine therapy reduced iron serum concentrations, ie iron absorption, significantly (p less than 0.05) when compared to the control, bicarbonate and phosphate groups. This study provides evidence that efforts to form digestive tract complexation of iron with bicarbonate or phosphate are of no value.

Administration, Oral↗
PubMed1987

Source of iron in neutrophil-mediated killing of endothelial cells.

Recently we have shown that human neutrophils activated with phorbol ester are cytotoxic for cultured bovine pulmonary artery endothelial cells in an iron-dependent manner. By using the ferric iron chelator deferoxamine mesylate, we have now investigated the source of the iron. Pretreatment of neutrophils with deferoxamine mesylate affected neither their production of O2- nor their cytotoxicity for endothelial cells after addition of phorbol ester. However, similar pretreatment of endothelial cells with deferoxamine mesylate, followed by washing of the cells, resulted in a persistent presence of chelator associated with the endothelial cells and high degrees of protection of endothelial cells from cytotoxicity. The protection was dependent on the amount of chelator used and on the duration of exposure of the endothelial cells to the chelator. These data suggest that iron, which plays an important role in oxygen radical-mediated killing of endothelial cells by neutrophils, is derived from the target (endothelial) cells.

Animals↗
PubMedDate not supplied

Aluminum-related osteomalacia in renal-failure patients.

The pathophysiology, clinical presentation, prevention, and treatment of aluminum-related osteomalacia in renal-failure patients are reviewed. Aluminum-related osteomalacia can develop in patients exposed to high concentrations of aluminum either in dialysis solutions or through gastrointestinal aluminum absorption from aluminum-containing antacids used to treat hyperphosphatemia. Although the exact etiology of aluminum-related osteomalacia is unknown, aluminum is believed to inhibit bone mineralization by forming an inhibitory complex with citric acid at physiologic concentrations. The complex is deposited along bone mineralization fronts and in bone marrow. The major symptoms of aluminum-related osteomalacia include skeletal pain, fractures, and vertebral collapse. The disease is difficult to diagnose because patients may have normal or slightly elevated serum concentrations of calcium, phosphate, alkaline phosphatase, and parathyroid hormone. Direct measurement of bone aluminum content (using biopsy) is often needed to confirm diagnosis. The aluminum-chelating agent deferoxamine mesylate can be used to measure bone aluminum content indirectly. Aluminum intoxication can be managed either by preventing exposure to aluminum or by removing deposited aluminum from bone. New standards restrict aluminum content in dialysis solutions, and prevention now focuses on the use of aluminum-free phosphate binders for treatment of hyperphosphatemia. Calcium carbonate may be as effective as aluminum-containing antacids in controlling serum phosphate concentrations, but it should be used cautiously in patients who are hypercalcemic or at risk of developing metastatic calcification. Chelation therapy with deferoxamine has improved the symptoms and bone histology in a small number of patients. Clinical improvements have been seen in patients receiving intravenous deferoxamine 2-6 g per week for 20 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗
PubMed1994

Yersinia enterocolitica infection in a patient with sickle cell disease after exposure to chitterlings.

PURPOSE: We describe certain clinical, epidemiologic, and host-susceptibility features of Yersinia enterocolitica infection in the context of a patient with underlying risk factors. PATIENTS AND METHODS: A 10-year-old black girl with sickle cell disease receiving chelation therapy for iron overload resulting from chronic transfusion therapy was admitted with acute abdominal pain and fever. RESULTS: Upon hospital admission, differential diagnoses included enterocolitis, appendicitis, and vasoocclusive crisis. On the 6th hospital day, the patient's stool culture became positive for Y. enterocolitica. Household exposure to raw pork intestines (chitterlings) was the presumed source of the infection. Deferoxamine therapy was withheld, and antibiotic therapy was administered with subsequent clinical improvement. CONCLUSIONS: Y. enterocolitica infection should be considered as a cause of abdominal pain mimicking appendicitis in patients with underlying risk factors (including certain sickle cell patients). History of exposure to raw or undercooked pork products and appropriate cultures should be obtained. Deferoxamine therapy should be withheld in iron-overloaded patients presenting with such symptoms because deferoxamine and iron overload constitute independent risk factors for Yersinia infection. Such patients should be advised to avoid potential exposures to this pathogen.

Anemia, Sickle Cell↗
PubMed1993

[A study on the protective effect of metallic chelators on ischemia-reperfusion injury of isolated rat heart].

A Langendorff isolated rat heart preparation was used to determine the effect of the metallic chelators, deferoxamine and penicillamine on the extent of myocardial ischemia reperfusion injury. Each heart was subjected to 15-60 minutes of total ischemia at 37 degrees C followed by 15-60 minutes of reperfusion with either saline, deferoxamine (0.61 mmol/L), or penicillamine (30 mmol/L) treated perfusate. Reperfusion injury was assessed by the production of free radicals with electronic spin resonance spectroscopy and spin trap PBN, by the amount of creatine phospholipase released into the perfusate, by the changes in the myocardial vascular resistance, and by pathologic examination of myocardium. The results showed that the drug treated groups released significantly less radical adducts of PBN (P < 0.01) and creatine phosphokinase into the perfusate than the saline treated group (P < 0.01). The mean vascular resistance significantly increased in the saline treated group than in the drug treated groups (P < 0.01). Ultrastructural examination showed prominent attenuation of mitochondrial swelling in drug treated groups in comparison with the saline one. These findings indicated that both deferoxamine and penicillamine can protect the isolated rat heart from ischemia reperfusion injury. The possible mechanism of which is that metallic chelators block the transitional metal-catalyzed fenton reaction, and subsequently decrease the production of hydroxyl radical.

Animals↗
PubMed1993

Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals.

BACKGROUND: Cardiopulmonary bypass and crystalloid cardioplegia may lead to endothelial dysfunction in the coronary microcirculation. The aim of the present study was to examine whether the alteration of endothelium-dependent microvascular responses may be related to the generation of oxygen-derived free radicals. METHODS AND RESULTS: Pigs (30 kg) were heparinized and placed on cardiopulmonary bypass. The hearts were arrested for 1 hour with either plain hypothermic, hyperkalemic (25 mEq/L) crystalloid cardioplegic solution (n = 10) or crystalloid cardioplegic solution containing either deferoxamine (n = 8) or manganese superoxide dismutase (n = 6). Hearts were then reperfused for 1 hour while the pigs were separated from cardiopulmonary bypass. Noninstrumented pigs were used as controls (n = 8). Coronary microarteries (120 to 190 microns in diameter) were studied in vitro in a pressurized (40 mm Hg), no-flow state with videomicroscopy and electronic dimension analysis. After precontraction of microvessels, the endothelium-dependent and -independent agents were applied extraluminally. Serotonin caused a slight dilation of control vessels (percent dilation of acetylcholine-induced preconstriction at 10 mumol/L drug concentration, 5 +/- 8%; P < .05 versus crystalloid cardioplegia group) and a significant contractile response after crystalloid cardioplegia (-28 +/- 10%). Bradykinin elicited near complete relaxation of control vessels (96 +/- 3%, P < .05), whereas it caused considerably less relaxation after cardioplegia (33 +/- 9%). The addition of either deferoxamine or superoxide dismutase to the cardioplegic solution significantly (but not completely) preserved vasomotor responses of coronary microvessels to serotonin (9 +/- 6% and 11 +/- 4%, respectively; P < .05) or bradykinin (72 +/- 4% and 87 +/- 3%, respectively; P < .05). Endothelium-independent relaxations of vessels in response to sodium nitroprusside were similar in all groups. CONCLUSIONS: Either the hydroxyl radical synthesis inhibitor deferoxamine or manganese superoxide dismutase preserves endothelium-dependent relaxation during crystalloid cardioplegia-reperfusion. Therefore, ischemic cardioplegia-reperfusion-induced endothelial dysfunction is at least partially mediated by the generation of oxygen-derived free radicals.

Animals↗
PubMed1993

D-CECaT: a breakthrough for patients with neuroblastoma.

In view of the high relapse rate following chemotherapy for patients with advanced neuroblastoma (NB) and primitive neuroectodermal tumors (PNET), we designed a novel chemotherapy program which incorporated the iron chelator deferoxamine. The purpose of the deferoxamine was to sensitize the cells to standard chemotherapy. The D-CECaT regimen contained (in mg/m2): deferoxamine 4500 during days 1-5; cyclophosphamide 600 mg over days 6 and 7; etoposide 300 mg over days 7 and 8; carboplatin 100 mg over days 7 and 8; and thiotepa 30 mg over days 6-8. Between October 1989 and May 1992 we entered 23 advanced NB and two PNET patients. Sepsis occurred in four courses, nausea and vomiting in 30 courses, and 50 courses required blood and platelets. Responses observed in previously untreated patients with stage III NB: six out of six CR (17+ to 41+ months), with stage IV NB, nine out of 11 CR (14+ to 28+ months), two out of 11 VGPR (22+ months), with stage IV PNET two out of two CR (1+ to 35+ months). With previously treated and failed stage IV NG, two out of six VGPR for 19+ and 20 months, and four out of six PR 1, 8, 9 and 11 months. Median survival for 19 new patients was 22+ months (6 to 41+ months; two patients in CR died at 7 months during adjuvant autologous marrow transplant). In conclusion, D-CECaT is an effective initial cytoreductive regimen for advanced stage NB/PNET patients. Additional patients and studies are required to determine its use as an alternative to autologous bone marrow transplantation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Myocardial protection in the occlusion/reperfusion dog model: the role of ischemic necrosis vs reperfusion injury.

The present study was designed to assess the possibility of maximizing the effects of reperfusion by the association of the calcium channel blocker, verapamil and the iron chelator deferoxamine, to delay necrosis and avoid reperfusion injury. Sixty-four mongrel dogs (15 +/- 1.1 (SD) kg) were successfully subjected to 24 h of reperfusion following 90-min occlusion of the left anterior coronary artery. ECG and arterial pressure were monitored. The risk area (RA; % left ventricle (LV)) was determined by the infusion of Evans blue into the aortic root and the area of necrosis (AN; %RA) by triphenyltetrazolium chloride staining. Myocardial preservation was defined as %RA not necrosed calculated as (RA-AN)/RA x 100. RA was similar in all dogs, i.e., 33 +/- 2% LV (SD). There were no differences in arterial pressure, heart rate or double product among groups. Myocardial preservation was 60 +/- 13% RA in 9 control dogs submitted to reperfusion only (group C), and 58 +/- 18% RA in 17 dogs treated with deferoxamine (500 mg, iv), 30 min before reperfusion (group DF). Verapamil (0.2 mg/kg, iv) was given alone 15 min after occlusion to 15 dogs (group VP), followed by prereperfusion deferoxamine to 16 dogs (group VP+DF) and in two doses after occlusion and 15 min before reperfusion in 7 dogs (group VP+VP). Myocardial preservation was greater in the latter groups when compared to controls, namely 76 +/- 13% RA in group VP, 74 +/- 11% in group VP+DF and 73 +/- 9% in group VP+VP (P = 0.04 vs group C, ANOVA). The data suggest that the mechanism underlying this beneficial effect is mainly related to the retardation of necrosis progression. O2 free radicals or Ca(2+)-induced reperfusion injury do not play a major role.

Animals↗
PubMed1997

Iron overload is a risk factor for zygomycosis.

Well-recognized risk factors for zygomycosis include diabetic ketoacidosis, immunocompromise, and deferoxamine therapy for iron or aluminum overload, usually in patients undergoing kidney dialysis. We report a case of fatal nasal-orbital-cerebral zygomycosis in an 82-year-old man with known myelodysplasia and well-controlled diabetes. He was not receiving deferoxamine. Despite radical surgery and amphotericin B therapy, he died; primary hemochromatosis with gross iron overload was found post mortem. Experimental evidence suggests iron overload without deferoxamine therapy may be a risk factor for zygomycosis; the findings in this case would support this hypothesis.

Aged↗
PubMed1986

Influence of chelating agents on the toxicity, distribution and excretion of vanadium in mice.

The effects of the chelating agents Na2Ca-ethylendiaminetetraacetate (EDTA), Na3Ca-diethylentriaminepentaacetate (DTPA), L-cysteine, 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron) and deferoxamine mesylate and the reducing agent ascorbic acid on the toxicity, excretion and distribution of i.p. injected vanadium were studied in male Swiss mice. Chelating and reducing agents were administered intraperitoneally at doses equal to one-fourth of their respective LD50. To determine the effects of the various chelators on the mortality of vanadium, various doses of NaVO3 (0.30-1.20 mmol kg-1 i.p.) were given, followed immediately by one of the chelating or reducing agents. Survival was recorded at the end of 14 days. Significant increases in survival were noted with ascorbic acid, Tiron and deferoxamine, with ascorbic acid being the most effective. Deferoxamine and Tiron were the most effective in increasing the excretion of vanadium and reducing the concentration of vanadium found in various tissues. However, ascorbic acid appears to be the most effective agent in the prevention of vanadium intoxication.

Animals↗
PubMed1993

Effects of melatonin on isolated pulmonary artery and vein: role of the vascular endothelium.

The influence of melatonin on tension of isolated pulmonary vascular smooth muscle rings was examined in these experiments. Melatonin caused a dose-dependent relaxation of precontracted (30 mM KCl) pulmonary artery and pulmonary vein. Removal of the endothelium did not alter the relaxant response to melatonin in pulmonary artery. In pulmonary artery with endothelium intact, preincubation with indomethacin, but not L-NG-monomethyl-L-arginine (L-NMMA) or deferoxamine, antagonized the relaxant response to melatonin. In pulmonary artery with endothelium removed, preincubation with deferoxamine, but not indomethacin, phorbol esters, or lithium chloride, antagonized the relaxant response to melatonin. In pulmonary vein, removal of the endothelium significantly increased the maximum relaxation attained in response to melatonin. In pulmonary vein with endothelium intact, preincubation with indomethacin, but not L-NMMA or deferoxamine, antagonized the relaxant response to melatonin. On the other hand, preincubation of de-endothelialized pulmonary vein with lithium chloride significantly increased the relaxation response to melatonin. These experiments demonstrate that both pulmonary artery and vein relax in response to melatonin and the mechanisms are apparently different.

Animals↗
PubMed1993

Chemiluminescence in activated human neutrophils: role of buffers and scavengers.

Human neutrophils (PMNs) suspended in Hanks' balanced salt solution (HBSS), which are stimulated either by polycation-opsonized streptococci or by phorbol myristate acetate (PMA), generate nonamplified (CL), luminol-dependent (LDCL), and lucigenin-dependent chemiluminescence (LUCDCL). Treatment of activated PMNs with azide yielded a very intense CL response, but only a small LDCL or LUCDCL responses, when horse radish peroxidase (HRP) was added. Both CL and LDCL depend on the generation of superoxide and on myeloperoxidase (MPO). Treatment of PMNs with azide followed either by dimethylthiourea (DMTU), deferoxamine, EDTA, or detapac generated very little CL upon addition of HRP, suggesting that CL is the result of the interaction among H2O2, a peroxidase, and trace metals. In a cell-free system practically no CL was generated when H2O2 was mixed with HRP in distilled water (DW). On the other hand significant CL was generated when either HBSS or RPMI media was employed. In both cases CL was markedly depressed either by deferoxamine or by EDTA, suggesting that these media might be contaminated by trace metals, which catalyzed a Fenton-driven reaction. Both HEPES and Tris buffers, when added to DW, failed to support significant HRP-induced CL. Nitrilotriacetate (NTA) chelates of Mn2+, Fe2+, Cu2+, and Co2+ very markedly enhanced CL induced by mixtures of H2O2 and HRP when distilled water was the supporting medium. Both HEPES and Tris buffer when added to DW strongly quenced NTA-metal-catalyzed CL. None of the NTA-metal chelates could boost CL generation by activated PMNs, because the salts in HBSS and RPMI interfered with the activity of the added metals. CL and LDCL of activated PMNs was enhanced by aminotriazole, but strongly inhibited by diphenylene iodonium (an inhibitor of NADPH oxidase) by azide, sodium cyanide (CN), cimetidine, histidine, benzoate, DMTU and moderately by superoxide dismutase (SOD) and by deferoxamine LUCDCL was markedly inhibited only by SOD but was boosted by CN. Taken together, it is suggested that CL generated by stimulated PMNs might be the result of the interactions among, NADPH oxidase, (inhibitable by diphenylene iodonium), MPO (inhibitable by sodium azide), H2O2 probably of intracellular origin (inhibitable by DMTU but not by catalase), and trace metals that contaminate salt solutions. The nature of the salt solutions employed to measure CL in activated PMNs is critical.

Acridines↗
PubMed1988

Toxic consequence of the abrupt depletion of glutathione in cultured rat hepatocytes.

Cultured hepatocytes were exposed to two chemicals, dinitrofluorobenzene (DNFB) and diethyl maleate (DEM), that abruptly deplete cellular stores of glutathione. Upon the loss of GSH, lipid peroxidation was evidenced by an accumulation of malondialdehyde in the cultures followed by the death of the hepatocytes. Pretreatment of the hepatocytes with a ferric iron chelator, deferoxamine, or the addition of an antioxidant, N,N'-diphenyl-p-phenylenediamine (DPPD), to the culture medium prevented both the lipid peroxidation and the cell death produced by either DNFB or DEM. However, neither deferoxamine nor DPPD prevented the depletion of GSH caused by either agent. Inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or inhibition of catalase by aminotriazole sensitized the hepatocytes to the cytotoxicity of DNFB. In a similar manner, pretreatment with BCNU potentiated the cell killing by DEM. DPPD and deferoxamine protected hepatocytes pretreated with BCNU and then exposed to DNFB or DEM. These data indicate that an abrupt depletion of GSH leads to lipid peroxidation and cell death in cultured hepatocytes. It is proposed that GSH depletion sensitizes the hepatocyte to its constitutive flux of partially reduced oxygen species. Such an oxidative stress is normally detoxified by GSH-dependent mechanisms. However, with GSH depletion these activated oxygen species are toxic as a result of the iron-dependent formation of a potent oxidizing species.

Amitrole↗