Implication of DNA damage during reperfusion of ischemic myocardium.
Explore the source record for details and available documents.
8-Hydroxy-2'-Deoxyguanosine↗
Biomedical subjects
S J Stohs
Publications and source records attributed to S J Stohs.
Age-related changes in lipid peroxidation and antioxidant defense in Fischer 344 rats.
Explore the source record for details and available documents.
Aging↗
Cadmium-induced production of superoxide anion and nitric oxide, DNA single strand breaks and lactate dehydrogenase leakage in J774A.1 cell cultures.
The involvement of reactive oxygen species in the toxicity of cadmium (Cd) has been proposed. We have, therefore, examined the effects of this cation on the production of superoxide anion and nitric oxide and DNA single strand breaks in J774A.1 macrophage cells in culture as well as the effects on lactate dehydrogenase (LDH) leakage and cell viability. Following a 48-h incubation, over 2-fold increases in superoxide anion and nitric oxide (NO) production were observed at a Cd concentration of approximately 0.60 microM, while a 50% decrease in viability was observed at this concentration. LDH leakage paralleled the superoxide anion and nitric oxide production. Concentration-dependent increases in DNA single strand breaks (SSB) were observed after incubation with Cd with a maximum increase occurring at a concentration of approximately 0.40 microM. The results indicate that Cd is toxic to the J774A.1 cell line, and support the hypothesis that the toxicity may be due at least in part to an oxidative stress induced by the production of reactive oxygen species following exposure to this cation.
Animals↗
In vitro and in vivo induction of heat shock (stress) protein (Hsp) gene expression by selected pesticides.
The chloroacetamide insecticide alachlor, polyhalogenated cyclic hydrocarbons endrin and chlordane and the organophosphate pesticides chlorpyrifos and fenthion induce oxidative tissue damaging effects including lipid peroxidation and nuclear DNA-single strand breaks. The mechanism involved in the induction of oxidative stress by these xenobiotics is unknown. No information is available regarding whether these pesticides can induce the expression of heat shock (stress) protein (Hsp) genes as a common protective mechanism against tissue damage. The pesticides were administered p.o. individually to female Sprague-Dawley rats in two 0.25 LD50 doses at 0 h and 21 h. The animals were killed at 24 h, and liver, brain, heart and lung tissues were removed to examine the induction of Hsps by Western and Northern blot analysis. In a separate series of experiments, cultured neuroactive PC-12 cells were treated 24 h with 50, 100 or 200 nM concentrations of these pesticides. Alachlor, endrin, chlorpyrifos and fenthion induced Hsp89 alpha and Hsp89 beta in hepatic and brain tissues, as well as in cultured PC-12 cells. Chlordane induced some expression of Hsp89 alpha but not Hsp89 beta in the hepatic and brain tissues of treated rats. Some expression of Hsp89 beta was observed in lung tissues of endrin and alachlor treated animals. These findings were substantiated by Western blot analysis using Hsp90 antibody. Except chlordane all these pesticides induced enhanced synthesis of Hsp90 in cultured PC-12 cells. The results indicate striking tissue differences in the patterns of the Hsps induced by the pesticides which were used, and demonstrate that these pesticides can induce the expression of Hsp89 alpha and Hsp89 beta genes in various target organs of rats. The results support the hypothesis that these genes may be mechanistically involved in protecting tissues against oxidative stress induced by structurally diverse pesticides.
Acetamides↗
In vitro effects of a smokeless tobacco extract on the production of reactive oxygen species by human oral epidermal cells and rat hepatic mitochondria and microsomes, and peritoneal macrophages.
The possible role of reaction oxygen species in the toxicity of smokeless tobacco was explored. In order to determine possible sources of reactive oxygen species in response to smokeless tobacco, rat peritoneal macrophages (3 x 10(6)/ml) and hepatic mitochondria and microsomes (1 mg protein/ml) from untreated female Sprague-Dawley rats were incubated with an aqueous smokeless tobacco extract (STE) (200 micro g/ml). STE resulted in rapid increases in chemiluminescence with maximum increases occurring at approximately 6 min for the macrophages and 8 min for mitochondria and microsomes. Maximum increases in chemiluminescence of 1.4-, 3.2-, and 3.1-fold relative to control values occurred for macrophages, mitochondria, and microsomes, respectively. Hepatic mitochondria and microsomes (1 mg protein/ml) from female Sprague-Dawley rats were incubated at 37 degrees C for 60 min in the presence of 0-500 micro g/ml STE. Potential tissue damage was measured as lipid peroxidation, and dose-dependent increases of 1.1-2.4-fold occurred in mitochondria and microsomes. Pre-incubation with various oxygen free radical scavengers including superoxide dismutase (SOD) (100 micro g/ml), catalase (100 micro g/ml), SOD + catalase (100 micro g/ml each), mannitol (1.25 mmol/ml), and allopurinol (100 micro g/ml) inhibited STE (200 micro g/ml) induced lipid peroxidation by 15% to 70%. Previous studies in our laboratories strongly suggest that STE induces the production of oxygen free radicals which cause tissue-damaging effects. We therefore examined the cytotoxicity of STE by incubating cultured human oral epidermal carcinoma (KB) cells with STE, and assessing the release of the enzyme lactate dehydrogenase (LDH) into the media as an indicator of cellular membrane damage. The amount of LDH released by STE was both concentration- and time-dependent. The results demonstrate that oral cells, peritoneal macrophages, and hepatic mitochondria and microsomes produce reactive oxygen species following in vitro incubation with an aqueous extract of smokeless tobacco. Tissue damage in response to STE may occur as the result of reactive oxygen species production.
Animals↗
Cadmium-induced excretion of urinary lipid metabolites, DNA damage, glutathione depletion, and hepatic lipid peroxidation in Sprague-Dawley rats.
Recent studies have described lipid peroxidation to be an early and sensitive consequence of cadmium exposure, and free radical scavengers and antioxidants have been reported to attenuate cadmium-induced toxicity. These observations suggest that cadmium produces reactive oxygen species that may mediate many of the untoward effects of cadmium. Therefore, the effects of cadmium (II) chloride on reactive oxygen species production were examined following a single oral exposure (0.50 LD50) by assessing hepatic mitochondrial and microsomal lipid peroxidation, glutathione content in the liver, excretion of urinary lipid metabolites, and the incidence of hepatic nuclear DNA damage. Increases in lipid peroxidation of 4.0- and 4.2-fold occurred in hepatic mitochondria and microsomes, respectively, 48 h after the oral administration of 44 mg cadmium (II) chloride/kg, while a 65% decrease in glutathione content was observed in the liver. The urinary excretion of malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), and acetone (ACON) were determined at 0-96 h after Cd administration. Between 48 and 72 h posttreatment maximal excretion of the four urinary lipid metabolites was observed with increases of 2.2- to 3.6-fold in cadmium (II) chloride-treated rats. Increases in DNA single-strand breaks of 1.7-fold were observed 48 h after administration of cadmium. These results support the hypothesis that cadmium induces production of reactive oxygen species, which may contribute to the tissue-damaging effects of this metal ion.
Animals↗
Comparative teratological studies on TCDD, endrin and lindane in C57BL/6J and DBA/2J mice.
The teratogenic effects of endrin and lindane have been determined and compared to those induced by TCDD in the fetuses of C57BL/6J and DBA/2J mice after the administration of single oral doses to pregnant mice on day 12 of gestation. TCDD produced dose-dependent decreases in fetal weight, fetal thymic weight and placental weight, and dose-dependent increases in fetolethality, cleft palate formation and hydronephrosis at doses of 10-30 and 30-60 micrograms/kg body weight in C57BL/6J and DBA/2J mice, respectively. No maternal death was observed at the given doses in both strains of mice. Endrin (4.5 and 6 mg/kg body weight) and lindane (30 and 45 mg/kg body weight) produced significant decreases in fetal weight and placental weight in C57BL/6J and DBA/2J mice, and dose-dependent decreases in fetal thymic weight in C57BL/6J mice but not DBA/2J mice. Endrin and lindane caused 0-25 and 14-25% maternal deaths, respectively, at the above mentioned doses. Neither cleft plate nor hydronephrosis were induced by endrin or lindane in the two strains of mice. The results support the hypothesis that TCDD-induced cleft plate and hydronephrosis involve mechanisms that are Ah (aryl hydrocarbon) receptor mediated. However, other fetotoxic effects induced by TCDD, and the fetotoxic effects induced by endrin and lindane may involve additional unknown mechanisms that are not related to the Ah-receptor.
Abnormalities, Drug-Induced↗
Naphthalene-induced oxidative stress in rats and the protective effects of vitamin E succinate.
Quinone metabolites of naphthalene (NAP) are known to produce lipid peroxidation. However, the ability of naphthalene to induce oxidative stress in experimental animals has not been extensively investigated. Furthermore, the effects of vitamin E succinate [(+)-alpha-tocopherol acid succinate; VES] on naphthalene-induced oxidative stress and tissue damage were assessed. Female Sprague-Dawley rats were treated with a single oral dose of 1100 mg naphthalene/kg (0.50 LD50) in corn oil. Vitamin E succinate-treated rats received 100 mg VES/kg/day orally for 3 d before naphthalene treatment, and 40 mg VES/kg/d after NAP administration. Hepatic and brain tissues and urine samples were collected 0, 12, 24, 48, and 72 h after NAP treatment. Naphthalene treatment resulted in a 2.1-fold increase in lipid peroxidation in liver and brain mitochondria at the 24-h time point. Increases in hepatic and brain mitochondrial lipid peroxidation in VES plus NAP-treated rats were 39-46% less than NAP treated rats at 24 h. DNA-single strand breaks increased 3.0-fold in hepatic tissues in NAP treated rats, and increased only 1.6-fold in VES protected rats at the 24-h time point. Glutathione (GSH) decreased by 83 and 49% in hepatic and brain tissues, respectively, in NAP-treated rats at the 24-h time point, while GSH content in VES plus NAP-treated rats decreased 47 and 21% in hepatic and brain tissues, respectively, at this same time point. Microsomal membrane fluidity, a measurement of membrane damage, increased 1.9- and 1.7-fold in liver and brain tissues, respectively, in NAP-treated rats, and only 1.3- and 1.2-fold in NAP plus VES-treated rats at the 24-h time point. The urinary excretion of malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), and acetone (ACON) was determined at 0-96 h after NAP administration. Between 12-24 h after NAP administration maximal excretion of the four urinary lipid metabolites was observed, with increases of 4.5-, 2.7-, 2.3-, and 2.8-fold for MDA, FA, ACT, and ACON, respectively, at the 24-h time point. VES reduced the NAP-induced excretion of these urinary metabolites by 28-49% 24 h after NAP administration. These results support the hypothesis that NAP induces oxidative stress and tissue damage, and that vitamin E succinate provides significant protection.
Animals↗
Production of reactive oxygen species by gastric cells in association with Helicobacter pylori.
Reactive oxygen species (ROS) and Helicobacter pylori have been identified as pathogenic factors in several gastrointestinal disorders. Since little information is available regarding the mechanistic pathways of H. pylori-induced gastric injury, the potential role of ROS was investigated. The induction of ROS in gastric cells (GC) by H. pylori was assessed using chemiluminescence, cytochrome c reduction, nitrobluetetrazolium (NBT) reduction and lactate dehydrogenase (LDH) leakage. The dose-dependent protective abilities of selected ROS scavengers on LDH leakage were determined. Following incubation of GC with three strains of H. pylori (1:1), approximately 5.7-8.0 and 3.8-4.3 fold increases were observed in cytochrome c and NBT reduction, respectively, demonstrating production of ROS. Enhanced chemiluminescence responses of 2.1- and 3.7-fold were observed following incubation of GC with H. pylori (ATCC 43504) at ratios of 1:1 and 1:10, respectively. Approximately 2.2- and 3.5-fold increases in LDH leakage were observed at GC:H. pylori (ATCC 43504) ratios of 1:1 and 1:10, respectively. Substantial inhibition of LDH leakage from GC in the presence of H. pylori was observed following co-incubations with selected ROS scavengers with cimetidine serving as the best chemoprotectant. The antioxidants and H2-receptor antagonists had no effect on growth of H. pylori cells. This study demonstrates that H. pylori induces enhanced production of ROS in GC, and enhances membrane damage.
Antioxidants↗
Role of iron in ricin-induced lipid peroxidation and superoxide production.
Ricin has been shown to induce oxidative stress in the livers of mice in vivo. These studies examined ricin-induced hepatic microsomal lipid peroxidation in mice, and the modulation thereof by iron and desferrioxamine. In addition, the studies investigated the production of superoxide anion by microsomes, mitochondria, and macrophages. Ricin (25 micrograms/kg, in vivo) increased microsomal lipid peroxidation by approximately 1.8-fold relative to control animals. This effect was abrogated by adding desferrioxamine to the microsomes. Fe2+ increased lipid peroxidation approximately 15-fold and 5-fold when added to microsomes from control and ricin-treated animals, respectively. Adding ricin to microsomes from control animals, however, decreased lipid peroxidation in a concentration-dependent manner. Desferrioxamine decreased lipid peroxidation by 47% and 64% in the absence and presence of ricin (5 micrograms/ml), respectively. Ricin, added to mitochondria from untreated animals decreased lipid peroxidation by 26% and 17% in the presence and absence of Fe2+, respectively. The administration of ricin (5 and 25 micrograms/kg) to mice increased microsomal, mitochondrial and macrophage superoxide anion production, in a dose-dependent fashion. The results suggest that iron mediated production of superoxide anion may be involved in the process of oxidative stress induced by ricin.
Animals↗
In vitro and in vivo generation of reactive oxygen species, DNA damage and lactate dehydrogenase leakage by selected pesticides.
Reactive oxygen species may be involved in the toxicity of various pesticides and we have, therefore, examined the in vivo effects of structurally dissimilar polyhalogenated cyclic hydrocarbons (PCH), such as endrin and chlordane, chlorinated acetamide herbicides (CAH), such as alachlor, and organophosphate pesticides (OPS), such as chlorpyrifos and fenthion, on the production of hepatic and brain lipid peroxidation and DNA-single strand breaks (SSB), two indices of oxidative stress and oxidative tissue damage. The selected pesticides were administered p.o. to female Sprague-Dawley rats in two 0.25 LD50 doses at 0 h and 21 h and killed at 24 h. In a parallel set of experiments, we have determined the in vitro effects of these pesticides on the DNA-SSB and enhanced lactate dehydrogenase leakage (LDH) from neuroactive PC-12 cells in culture. In vitro production of reactive oxygen species by these pesticides was also assessed by determining the enhanced chemiluminescence responses of hepatic and brain homogenates. Following treatment of rats with endrin, chlordane, alachlor, chlorpyrifos and fenthion, increases of 2.8-, 3.0-, 4.2-, 4.3- and 4.8-fold were observed in hepatic lipid peroxidation, respectively, while at these same doses, increases in lipid peroxidation of 2.4-, 2.1-, 3.6-, 4.6- and 5.3-fold, respectively, were observed in brain homogenates. Increases of 4.4-, 3.9-, 1.6-, 3.0- and 3.5-fold were observed in hepatic DNA-SSB following treatment of the rats with endrin, chlordane, alachlor, chlorpyrifos and fenthion, respectively, while at these same doses, increases of 1.9-, 1.7-, 2.2-, 1.4-, 1.4-fold, respectively, were observed in brain nuclear DNA-SSB. Following in vitro incubation of hepatic and brain tissues with 1 nmol/ml of each of the five pesticides, maximum increases in chemiluminescence occurred within 4-7 min of incubation and persisted for over 10 min. Increases of 3.0-, 2.7-, 3.6-, 4.9- and 4.4-fold were observed in chemiluminescence following in vitro incubation of the liver homogenates with endrin, chlordane, alachlor, chlorpyrifos and fenthion, respectively, while increases of 1.7-, 1.8-, 2.0-, 3.4- and 3.7-fold, respectively, were observed in the brain homogenates. Increases of 2.2-, 2.3-, 2.9-, 2.9- and 3.4-fold were observed in the chemiluminescence responses in the liver homogenates of the animals treated with endrin, chlordane, alachlor, chlorpyrifos and fenthion, respectively, while increases of 1.8-, 2.0-, 3.2-, 2.9- and 2.4-fold, respectively, were observed in the brain homogenates. Cultured neuroactive PC-12 cells were incubated with the pesticides and the release of the enzyme lactate dehydrogenase (LDH) into the media as an indicator of cellular damage and cytotoxicity was examined. Maximal release of LDH from cultured PC-12 cells was observed at 100 nM concentrations of the pesticides. Increases of 2.3-, 2.5-, 2.8-, 3.1 and 3.4-fold were observed in LDH leakage following incubation of the PC-12 cells with endrin, chlordane, alachlor, chlorpyrifos and fenthion, respectively. Following incubation of the cultured PC-12 cells with 100 nM concentrations of these same pesticides, increases in DNA-SSB of 2.5-, 2.2-, 2.1-, 2.4- and 2.5-fold, respectively, were observed. The results clearly demonstrate that these different classes of pesticides induce production of reactive oxygen species and oxidative tissue damage which may contribute to the toxic manifestations of these xenobiotics. Reactive oxygen species may serve as common mediators of programmed cell death (apoptosis) in response to many toxicants and pathological conditions.
Acetamides↗
Adriamycin-induced hepatic and myocardial lipid peroxidation and DNA damage, and enhanced excretion of urinary lipid metabolites in rats.
Adriamycin produces clinically useful responses in a variety of human cancers including lymphomas, leukemias, and solid tumors. However, the toxicity of adriamycin has limited its usefulness. Iron-catalyzed free radical reactions as the peroxidation of membrane lipids, inactivation of critical enzymes, and the inhibition of DNA, RNA and protein synthesis in heart, liver and kidney have been implicated in the toxicity of adriamycin. In order to further assess the role of oxidative stress in the toxicity of adriamycin, the effects of adriamycin were examined on the urinary excretion of lipid metabolites at 0, 6, 12, 24, 48 and 72 h post-treatment, and on myocardial and hepatic lipid peroxidation and nuclear DNA single strand breaks at 24 h post-treatment following single oral and intravenous (i.v.) doses of 10 mg/kg adriamycin. Urinary malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT) and acetone (ACON) excretion was significantly increased at all time points examined. Following the oral administration of adriamycin, maximum excretion of MDA, FA, ACT and ACON of 6.2-, 2.7-, 3.7- and 2.2-fold relative to control values, respectively, occurred 24 h after treatment. However, following the i.v. administration of adriamycin, greatest increases in excretion of MDA, FA and ACT reaching 6.9-, 3.3- and 6.3-fold relative to control values, respectively, were observed 6 h after treatment, while the greatest increase in ACON excretion of 4.2-fold relative to control values occurred 12 h post-treatment. Following oral and i.v. administration of adriamycin, significant increases were observed in myocardial and hepatic lipid peroxidation in mitochondrial and microsomal membranes, and myocardial and hepatic nuclei DNA single strand breaks 24 h after treatment. The results indicate that adriamycin administration induces myocardial and hepatic lipid peroxidation which may be responsible for enhanced excretion of urinary lipid metabolites as a result of membrane damage, and also induces enhanced DNA damage. These effects may be due to adriamycin-induced production of reactive oxygen species.
Acetaldehyde↗
Chromium-induced production of reactive oxygen species, DNA single-strand breaks, nitric oxide production, and lactate dehydrogenase leakage in J774A.1 cell cultures.
The involvement of oxidative stress in the toxicity of chromium (VI) and chromium (III) has been proposed. We have therefore examined the effects of these cations on the production of superoxide anion, nitric oxide (NO), and DNA single strand breaks (SSB) in J774A.1 macrophage cells in culture as well as the effects on lactate dehydrogenase (LDH) leakage and cell viability. Following a 48 hour incubation, over twofold increases in superoxide anion and NO production were observed at concentrations of approximately 0.30 and 50 microM for Cr (VI) and Cr (III), respectively. The patterns of cell viability and LDH leakage paralleled superoxide anion and NO production for Cr (VI) and Cr (III). A 50% decrease in viability was observed at approximately the concentrations that produced a twofold increase in superoxide and NO production. Concentration-dependent increases in DNA-SSB were observed after incubation with Cr (III) with maximum increases occurring at a concentration of approximately 60 microM. Cr (VI) had no effect on the incidence of DNA-SSB at any of the tested concentrations. The results indicate that Cr (VI) and Cr (III) are toxic to the J774A.1 cell line, and the toxicity may be due at least in part to an oxidative stress induced by the production of reactive oxygen species.
Cell Line↗
Protective effects of free radical scavengers and antioxidants against smokeless tobacco extract (STE)-induced oxidative stress in macrophage J774A.1 cell cultures.
Previous studies have demonstrated that an aqueous smokeless tobacco extract (STE) administered in an acute oral dose to rats induces an enhanced induction of hepatic mitochondrial and microsomal lipid peroxidation, hepatic nuclear DNA single strand breaks, enhanced excretion of urinary lipid metabolites, including malondialdehyde, formaldehyde, acetaldehyde and acetone, and increased production of nitric oxide (NO) by peritoneal macrophage cells. These observations indicate that STE induces the production of oxygen free radicals. We have therefore examined the in vitro incubation of cultured J774A.1 macrophage cells with STE on the release of the enzyme lactate dehydrogenase (LDH) into the media as an indicator of cellular membrane damage and cytotoxicity. The amount of LDH released by STE was both concentration- and time-dependent. The cytotoxicity of STE to macrophage J774A.1 cells in culture was further determined from percent viability after various periods of incubation. The addition of 250 micrograms STE/ml to the cultured J774A.1 cells resulted in a 2.9-fold increase in the release of LDH. Individual coincubation with superoxide dismutase (SOD), catalase, mannitol, and allopurinol had no significant effect on the release of LDH into the culture medium, while a combination of the four free radical scavengers resulted in a 59% decrease in the STE-induced release of LDH. At 75 microM concentrations of viramine E and vitamin E succinate, approximately 28% and 41% inhibitions were observed in STE-induced LDH leakage, respectively. Taken together with previous studies, the results indicate that STE activates macrophage cells, resulting in the production of reactive oxygen species.(ABSTRACT TRUNCATED AT 250 WORDS)
Allopurinol↗
Evidence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced tissue damage in fetal and placental tissues and changes in amniotic fluid lipid metabolites of pregnant CF1 mice.
Pregnant CF1 mice were given 30 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg or the vehicle as a single i.p. dose on day 12 of gestation and killed 48 h later. Increases in DNA elution rate constants (single strand breaks) in fetal and placental nuclei of 1.8- and 2.3-fold, respectively, were observed. Increases in lipid peroxidation (thiobarbituric acid reactive substances) in placental and fetal tissues of 1.9- and 1.5-fold, respectively, were also observed. TCDD administration produced increases in the amniotic fluid levels of the lipid metabolites malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), and acetone (ACON) of 2.5-, 1.6-, 1.4-, and 1.6-fold, respectively relative to control animals. The results suggest that reactive oxygen species may participate in the teratogenic effects of TCDD.
Acetaldehyde↗
Chromium-induced excretion of urinary lipid metabolites, DNA damage, nitric oxide production, and generation of reactive oxygen species in Sprague-Dawley rats.
Chromium and its salts induce cytotoxicity and mutagenesis, and vitamin E has been reported to attenuate chromate-induced cytotoxicity. These observations suggest that chromium produces reactive oxygen species which may mediate many of the untoward effects of chromium. We have therefore examined and compared the effects of Cr(III) (chromium chloride hexahydrate) and Cr(VI) (sodium dichromate) following single oral doses (0.50 LD50) on the production of reactive oxygen species by peritoneal macrophages, and hepatic mitochondria and microsomes in rats. The effects of Cr(III) and Cr(VI) on hepatic mitochondrial and microsomal lipid peroxidation and enhanced excretion of urinary lipid metabolites as well as the incidence of hepatic nuclear DNA damage and nitric oxide (NO) production were also examined. Increases in lipid peroxidation of 1.8- and 2.2-fold occurred in hepatic mitochondria and microsomes, respectively, 48 hr after the oral administration of 25 mg Cr(VI)/kg, while increases of 1.2- and 1.4-fold, respectively, were observed after 895 mg Cr(III)/kg. The urinary excretion of malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT) and acetone (ACON) were determined at 0-96 hr after Cr administration. Between 48 and 72 hr post-treatment, maximal excretion of the four urinary lipid metabolites was observed with increases of 1.5- to 5.4-fold in Cr(VI) treated rats. Peritoneal macrophages from Cr(VI) treated animals 48 hr after treatment resulted in 1.4- and 3.6-fold increases in chemiluminescence and iodonitrotetrazolium reduction, indicating enhanced production of superoxide anion, while macrophages from Cr(III) treated animals showed negligible increases. Increases in DNA single strand breaks of 1.7-fold and 1.5-fold were observed following administration of Cr(VI) and Cr(III), respectively, at 48 hr post-treatment. Enhanced production of NO by peritoneal exudate cells (primarily macrophages) was monitored following Cr(VI) administration at both 24 and 48 hr post-treatment with enhanced production of NO being observed at both timepoints. The results indicate that both Cr(VI) and Cr(III) induce an oxidative stress at equitoxic doses, while Cr(VI) induces greater oxidative stress in rats as compared with Cr(III) treated animals.
Acetaldehyde↗
Oxidative stress induced by chronic administration of sodium dichromate [Cr(VI)] to rats.
Chromium occurs in the workplace primarily in the valence forms Cr(III) and Cr(VI). Recent studies have demonstrated that sodium dichromate [Cr(VI)] induces greater oxidative stress as compared with Cr(III), as indicated by the production of reactive oxygen species by peritoneal macrophages and hepatic mitochondria and microsomes, and enhanced excretion of urinary lipid metabolites and hepatic DNA-single strand breaks (SSB) following acute oral administration of Cr(III) and Cr(VI). We have therefore examined the chronic effects of sodium dichromate dihydrate [Cr(VI); 10 mg (33.56 mumol)/kg/day] on hepatic mitochondrial and microsomal lipid peroxidation, enhanced excretion of urinary lipid metabolites including malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), acetone (ACON) and propionaldehyde (PROP), and hepatic DNA damage over a period of 90 days. The maximal increases in hepatic lipid peroxidation and DNA damage were observed at approximately 45 days of treatment. Maximum increases in the urinary excretion of MDA, FA, ACT, ACON and PROP were 3.2-, 2.6-, 4.1-, 3.3- and 2.1-fold, respectively, while a 5.2-fold increase in DNA-SSB was observed. The results clearly indicate that chronic sodium dichromate administration induces oxidative stress resulting in tissue damaging effects which may contribute to the toxicity and carcinogenicity of hexavalent chromium.
Acetaldehyde↗
Oxidative mechanisms in the toxicity of metal ions.
The role of reactive oxygen species, with the subsequent oxidative deterioration of biological macromolecules in the toxicities associated with transition metal ions, is reviewed. Recent studies have shown that metals, including iron, copper, chromium, and vanadium undergo redox cycling, while cadmium, mercury, and nickel, as well as lead, deplete glutathione and protein-bound sulfhydryl groups, resulting in the production of reactive oxygen species as superoxide ion, hydrogen peroxide, and hydroxyl radical. As a consequence, enhanced lipid peroxidation. DNA damage, and altered calcium and sulfhydryl homeostasis occur. Fenton-like reactions may be commonly associated with most membranous fractions including mitochondria, microsomes, and peroxisomes. Phagocytic cells may be another important source of reactive oxygen species in response to metal ions. Furthermore, various studies have suggested that the ability to generate reactive oxygen species by redox cycling quinones and related compounds may require metal ions. Recent studies have suggested that metal ions may enhance the production of tumor necrosis factor alpha (TNF alpha) and activate protein kinase C, as well as induce the production of stress proteins. Thus, some mechanisms associated with the toxicities of metal ions are very similar to the effects produced by many organic xenobiotics. Specific differences in the toxicities of metal ions may be related to differences in solubilities, absorbability, transport, chemical reactivity, and the complexes that are formed within the body. This review summarizes current studies that have been conducted with transition metal ions as well as lead, regarding the production of reactive oxygen species and oxidative tissue damage.
Animals↗