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search:  n-acetylcysteine and metal

Life Flow One
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HealthGate Documents

Record 1 from database: MEDLINE
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Title

Air pollution particles induce IL-6 gene expression in human airway epithelial cells via NF-kappaB activation.

Author

Quay JL; Reed W; Samet J; Devlin RB

Address

National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, NC 27711, USA.

Source

Am J Respir Cell Mol Biol, 1998 Jul, 19:1, 98-106

Abstract

Fine particles in the air have been associated with increased mortality and morbidity. Particulate air pollution is a complex mixture which varies by region and includes a number of components including residual oil fly ash (ROFA), a byproduct of power plant and industry fuel-oil combustion. Human airway epithelial cells exposed to ROFA release inflammatory cytokines including interleukin (IL)-6, IL-8, and tumor necrosis factor. Expression of these genes is dependent upon pretranscriptional binding of cis regulatory elements, including nuclear factor kappaB (NF-kappaB). To investigate the role of NF-kappaB in the particulate-induced IL-6 response, we exposed human airway epithelial cells (BEAS-2B) to ROFA in vitro. ROFA stimulated a time- and dose-dependent increase in IL-6 messenger RNA (mRNA), which was preceded by the activation of nuclear proteins binding to the NF-kappaB sequence motif in the IL-6 promoter. Transient transfection of BEAS-2B cells with the 5' promoter region of the IL-6 gene linked to a luciferase reporter gene confirmed that NF-kappaB binding is necessary for the transcription of IL-6 mRNA. The IL-6 response was inhibited by the metal chelator deferoxamine and the free radical scavenger N-acetyl-L-cysteine, suggesting that the activation of NF-kappaB may be mediated through reactive oxygen intermediates generated by transition metals found in ROFA. Activation of NF-kappaB may therefore be a critical first step in the inflammatory cascade following exposure to particles generated by oil combustion.

Language of Publication

English

Unique Identifier

98315034

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MeSH Heading (Major)

Air Pollutants|*TO; Bronchi|CY/DE/*ME; Gene Expression Regulation|*; Interleukin-6|*GE; Metals|*TO; NF-kappa B|*ME

MeSH Heading

Acetylcysteine|PD; Carbon|TO; Cell Line; Deferoxamine|PD; DNA|ME; Epithelial Cells|CY/DE; Free Radical Scavengers|PD; Fuel Oils; Human; Promoter Regions (Genetics); RNA, Messenger|GE/ME; Transfection

Publication Type

JOURNAL ARTICLE

ISSN

1044-1549

Country of Publication

UNITED STATES

Record 2 from database: MEDLINE
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Title

Effects of oxidants and antioxidants on nuclear factor kappa B activation in three different cell lines: evidence against a universal hypothesis involving oxygen radicals.

Author

Brennan P; ONeill LA

Address

Biochemistry Department, Trinity College, Dublin, Ireland.

Source

Biochim Biophys Acta, 1995 Jan, 1260:2, 167-75

Abstract

A model for NF kappa B activation involving reactive oxygen intermediates has recently been proposed. We have explored this model in three cell lines, Jurkat T cells, EL4.NOB-1 T cells and KB epidermal cells using hydrogen peroxide and two physiological activators of NF kappa B, interleukin-1 (IL1) and tumor necrosis factor (TNF) as stimuli. In agreement with earlier studies hydrogen peroxide activated NF kappa B in Jurkat, although only at much higher concentrations (10 mM) than those previously reported. However, hydrogen peroxide failed to activate in the two other cell lines under a range of conditions. Similarly, N-acetylcysteine only proved inhibitory in hydrogen peroxide and TNF treated Jurkat and failed to inhibit IL1 and TNF-activated NF kappa B in EL4.NOB-1 and KB cells respectively. N-Acetylcysteine inhibited IL1-induced interleukin-2 in EL4, however, demonstrating that N-acetylcysteine was biologically active. These results suggest that the reactive oxygen model of NF kappa B activation may be cell-type restricted. In contrast to the results with N-acetylcysteine, the antioxidant and metal chelator, pyrolidine dithiocarbamate (PDTC) inhibited NF kappa B activation, although these effects may be unrelated to any antioxidant properties. PDTC also inhibited IL1-induced interleukin-2. Finally, studies with the pro-oxidant diamide showed that this could not activate NF kappa B in any of the cells and in contrast proved inhibitory. The results from this study therefore suggest that the reactive oxygen model of NF kappa B activation may be restricted to certain cell types and that the presence of such a system is not required for the activation of NF kappa B by IL1 and TNF.

Language of Publication

English

Unique Identifier

95143273

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MeSH Heading (Major)

Hydrogen Peroxide|*PD; Interleukin-1|*PD; NF-kappa B|*ME; Oxygen|*ME; Tumor Necrosis Factor|*PD

MeSH Heading

Acetylcysteine|PD; Animal; Base Sequence; Cell Line; Comparative Study; Free Radicals; Human; Mice; Molecular Sequence Data; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0006-3002

Country of Publication

NETHERLANDS

Record 3 from database: MEDLINE
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Title

Clinical applications of N-acetylcysteine.

Author

Kelly GS

Address

Alternative Medicine Review, Greenwich, CT.

Source

Altern Med Rev, 1998 Apr, 3:2, 114-27

Abstract

N-acetylcysteine (NAC), the acetylated variant of the amino acid L-cysteine, is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers. Administration of NAC has historically been as a mucolytic agent in a variety of respiratory illnesses; however, it appears to also have beneficial effects in conditions characterized by decreased GSH or oxidative stress, such as HIV infection, cancer, heart disease, and cigarette smoking. An 18-dose oral course of NAC is currently the mainstay of treatment for acetaminophen-induced hepatotoxicity. N-acetylcysteine also appears to have some clinical usefulness as a chelating agent in the treatment of acute heavy metal poisoning, both as an agent capable of protecting the liver and kidney from damage and as an intervention to enhance elimination of the metals.

Language of Publication

English

Unique Identifier

98238108

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MeSH Heading (Major)

Acetylcysteine|AE/PD/*TU; Free Radical Scavengers|AE/PD/*TU

MeSH Heading

Antiviral Agents|TU; Expectorants|TU; Glutathione|BI; Human; Poisoning|DT

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

1089-5159

Country of Publication

UNITED STATES

Record 4 from database: MEDLINE
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Title

Pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kappa B (NF-kappa B) activation, prevents apoptosis in human promyelocytic leukemia HL-60 cells and thymocytes.

Author

Bessho R; Matsubara K; Kubota M; Kuwakado K; Hirota H; Wakazono Y; Lin YW; Okuda A; Kawai M; Nishikomori R; et al

Address

Department of Pediatrics, Faculty of Medicine, Kyoto University, Japan.

Source

Biochem Pharmacol, 1994 Nov, 48:10, 1883-9

Abstract

We examined the effect of pyrrolidine dithiocarbamate (PDTC), which potently blocks the activation of nuclear factor kappa B (NF-kappa B), on the induction of apoptosis by a variety of agents. Treatment of a human promyelocytic leukemia cell line, HL-60, with 10 micrograms/mL etoposide or 2 microM 1-beta-D-arabinofuranosylcytosine induced NF-kappa B activation within 1 hr and subsequently caused apoptosis within 3-4 hr. The simultaneous addition of 50-500 microM PDTC with these agents blocked NF-kappa B activation and completely abrogated both morphologically apoptotic changes and internucleosomal DNA fragmentation for up to 6 hr. However, PDTC failed to inhibit the endonuclease activity contained in the whole cell lysates. The inhibitory effect of PDTC was also observed in etoposide- and dexamethasone-induced apoptosis in human thymocytes at a concentration of 1-10 microM. Since PDTC has both antioxidant and metal-ion chelating activities, we tested the effects of N-acetyl-L-cysteine (NAC) (antioxidant) or o-phenanthroline (OP) (metal-ion chelator) on the induction of apoptosis. Pretreatment of HL-60 cells or thymocytes with 100-500 microM OP for 2 hr, but not 10-60 mM NAC, suppressed subsequent occurrence of apoptosis induced by etoposide. These results suggest that the activation of NF-kappa B plays an important role in the apoptotic process of human hematopoietic cells.

Language of Publication

English

Unique Identifier

95077537

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MeSH Heading (Major)

Apoptosis|*DE; Leukemia, Promyelocytic, Acute|*PA; NF-kappa B|*AI; Pyrrolidines|*PD; T-Lymphocytes|CY/*DE; Thiocarbamates|*PD

MeSH Heading

Acetylcysteine|PD; Base Sequence; Cytarabine|PD; Endonucleases|AI; Etoposide|PD; Human; Molecular Sequence Data; Oligodeoxyribonucleotides; Phenanthrolines|PD; Thymus Gland|CY; Tumor Cells, Cultured

Publication Type

JOURNAL ARTICLE

ISSN

0006-2952

Country of Publication

ENGLAND

Record 5 from database: MEDLINE
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Title

Regulation of p53 by metal ions and by antioxidants: dithiocarbamate down-regulates p53 DNA-binding activity by increasing the intracellular level of copper.

Author

Verhaegh GW; Richard MJ; Hainaut P

Address

Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.

Source

Mol Cell Biol, 1997 Oct, 17:10, 5699-706

Abstract

Mutations in the p53 tumor suppressor gene frequently fall within the specific DNA-binding domain and prevent the molecule from transactivating normal targets. DNA-binding activity is regulated in vitro by metal ions and by redox conditions, but whether these factors also regulate p53 in vivo is unclear. To address this question, we have analyzed the effect of pyrrolidine dithiocarbamate (PDTC) on p53 DNA-binding activity in cell lines expressing wild-type p53. PDTC is commonly regarded as an antioxidant, but it can also bind and transport external copper ions into cells and thus exert either pro- or antioxidant effects in different situations. We report that PDTC, but not N-acetyl-L-cysteine, down-regulated the specific DNA-binding activity of p53. Loss of DNA binding correlated with disruption of the immunologically "wild-type" p53 conformation. Using different chelators to interfere with copper transport by PDTC, we found that bathocuproinedisulfonic acid (BCS), a non-cell-permeable chelator of Cu1+, prevented both copper import and p53 down-regulation. In contrast, 1,10-orthophenanthroline, a cell-permeable chelator of Cu2+, promoted the redox activity of copper and up-regulated p53 DNA-binding activity through a DNA damage-dependent pathway. We have previously reported that p53 protein binds copper in vitro in the form of Cu1+ (P. Hainaut, N. Rolley, M. Davies, and J. Milner, Oncogene 10:27-32, 1995). The data reported here indicate that intracellular levels and redox activity of copper are critical for p53 protein conformation and DNA-binding activity and suggest that copper ions may participate in the physiological control of p53 function.

Language of Publication

English

Unique Identifier

97459668

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MeSH Heading (Major)

Antioxidants|*PD; Chelating Agents|*PD; Copper|*ME; Proline|*AA/PD; Protein p53|BI/CH/DE/*ME; Thiocarbamates|*PD

MeSH Heading

Acetylcysteine|PD; Cell Cycle; Cell Line; Cyclins|BI; DNA|ME; DNA Damage; Human; Hydrogen Peroxide|PD; Intercalating Agents|PD; Ion Transport|DE; Lipid Peroxidation; Oxidation-Reduction; Oxidative Stress; Phenanthrolines|PD; Protein Binding|DE; Protein Conformation|DE; Proteins|PH; Support, Non-U.S. Gov't; Tumor Cells, Cultured

Publication Type

JOURNAL ARTICLE

ISSN

0270-7306

Country of Publication

UNITED STATES

Record 6 from database: MEDLINE
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Title

Concentration-dependent differential effects of N-acetyl-L-cysteine on the expression of HSP70 and metallothionein genes induced by cadmium in human amniotic cells.

Author

Abe T; Yamamura K; Gotoh S; Kashimura M; Higashi K

Address

Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan. abetetsu@med.uoeh-u.ac.jp

Source

Biochim Biophys Acta, 1998 Mar, 1380:1, 123-32

Abstract

Cadmium induces the expression of the 70 kDa heat shock protein (HSP70) and metallothionein (MT), both of which are considered to be associated with intracellular glutathione (GSH) metabolism in the cellular protection mechanism against cadmium-induced cellular injury. We determined the effects of N-acetyl-L-cysteine (NAC), which increases the intracellular GSH levels, on the induction of HSP70 and MT gene expression in a cultured cell line of human amniotic cells (WISH) exposed to CdCl2. The mRNA level of MT-II, a major isoform of MT genes, was more prominently increased than that of HSP70 when WISH cells were exposed to CdCl2 (5-15 microM, for 6 h). The treatment of WISH cells with 1.5 and 30 mM NAC for 2 h increased the intracellular GSH levels by 1.4- and 3.1-fold, respectively. Pretreatment of cells with 30 mM NAC significantly reduced both HSP70 and MT-II mRNA levels in the cells exposed to 50 microM CdCl2. This concentration of NAC also efficiently suppressed the cadmium-induced lethality. On the contrary, pretreatment with 1.5 mM NAC suppressed only the induction of HSP70 gene expression in the 50 microM CdCl2-treated cells, and did not inhibit the metal toxicity. However, this low concentration of NAC efficiently suppressed lipid peroxidation which was increased by 50 microM CdCl2. Furthermore, this low concentration of NAC also decreased the CdCl2-induced gene expression of HSP32 which represents a general response to oxidative stress. Taken together, NAC seems to have at least two concentration-dependent functions in WISH cells exposed to CdCl2; the low concentration of NAC can suppress the induction of HSP70 gene expression as well as the increase of lipid peroxidation via an antioxidant pathway, while the high concentration of NAC can suppress the induction of MT-II mRNA as well as cadmium-induced cell death. Our present data suggest that changes in intracellular redox status, as reflected by GSH concentration, have more important effects on the induction of HSP70 mRNA rather than that of MT-II mRNA in human amniotic cells exposed to cadmium.

Language of Publication

English

Unique Identifier

98207682

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MeSH Heading (Major)

Acetylcysteine|AD/*PD; Cadmium|*TO; Heat-Shock Proteins 70|*GE; Metallothionein|*GE

MeSH Heading

Amnion; Cell Line; Dose-Response Relationship, Drug; Gene Expression|DE; Glutathione|ME; Human; Lipid Peroxidation|DE; RNA, Messenger|GE/ME; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0006-3002

Country of Publication

NETHERLANDS

Record 7 from database: MEDLINE
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Title

Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants.

Author

Vyth A; Timmer JG; Bossuyt PM; Louwerse ES; de Jong JM

Address

Department of Pharmacy E-0, University of Amsterdam, UK.

Source

J Neurol Sci, 1996 Aug, 139 Suppl:, 99-103

Abstract

Between 1983 and 1988 we treated 36 patients with sporadic amyotrophic lateral sclerosis (ALS) by an array of antioxidants and added other drugs to the regimen whenever a patient reported deterioration. Our customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E; N-acetylmethionine (NAM); and dithiothreitol (DTT) or its isomer dithioerythritol (DTE). Patients with a history of heavy exposure to metal were also given meso 2,3-dimercaptosuccinic acid (DMSA). NAC, NAM, DTT, and DTE were administered by subcutaneous injection or by mouth or by both routes, the other vitamins and DMSA by mouth alone. The hospital pharmacy supplied NAC and NAM injections fluid as 100 ml bottles of 5.0 and 5.85% solutions, respectively. DTT was delivered in special double-walled capsules of 200 mg. DTT/DTE injection fluid was added to the NAC and NAM bottles, the final DTT/DTE concentrations never exceeding 0.5%. DMSA was provided in 250 mg capsules. All of the 36 patients used NAC and DTT/DTE; 29 also used vitamins C and E; 21 also used NAM; and 7 also used DMSA, DMSA, NAM, vitamins C and E were tolerated well. In many patients, DTT, DTE, NAC and NAM induced pain, redness and swelling at the injection sites in that order of decreasing frequency. DTT and DTE did often and NAC did sometimes cause gastric pain, nausea and other abdominal discomfort. Comparison of survival in the treated group and in a cohort of untreated historical controls, disclosed a median survival of 3.4 years (95% confidence interval: 3.0-4.2) in the treated and of 2.8 (95% confidence interval 2.2-3.1) years in the control patients. This difference may be explained by self-selection of our highly motivated treated group and by its initial survival of diagnosis for an average of 8.5 months before onset of treatment. We conclude that antioxidants neither seem to harm ALS patients, nor do they seem to prolong survival.

Language of Publication

English

Unique Identifier

97055380

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MeSH Heading (Major)

Amyotrophic Lateral Sclerosis|*DT/*MO; Antioxidants|*AD

MeSH Heading

Acetylcysteine|AD; Administration, Oral; Capsules; Chelating Agents|AD; Dithioerythritol|AD; Dithiothreitol|AD; Free Radical Scavengers|AD; Gastric Juice|CH; Human; Injections, Subcutaneous; Methionine|AA/AD; Succimer|AD; Sulfhydryl Reagents|AD; Survival Analysis

Publication Type

CLINICAL TRIAL; JOURNAL ARTICLE

ISSN

0022-510X

Country of Publication

NETHERLANDS

Record 8 from database: MEDLINE
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Title

Does N-acetylcysteine increase the excretion of trace metals (calcium, magnesium, iron, zinc and copper) when given orally?

Author

Hjorts‡ E; Fomsgaard JS; Fogh-Andersen N

Address

Department of Anaesthesiology, Herlev Hospital, University of Copenhagen, Denmark.

Source

Eur J Clin Pharmacol, 1990, 39:1, 29-31

Abstract

N-Acetylcysteine (NAC) is known to decrease the exacerbation rate in patients with chronic bronchitis. It has also been shown that NAC has both an oxygen-radical scavenger and a heavy-metal chelating effect in high intravenous doses. In a study lasting 5 weeks, 10 healthy volunteers were treated with NAC 200 mg t.d.s. for two weeks. The concentrations of trace metals (Ca, Mg, Fe, Zn & Cu) in plasma were measured weekly and daily in a morning spot urine during the investigation. No significant change in plasma concentration or excretion was found during the two weeks of treatment, implying that additional administration of trace metals is unnecessary for patients treated perorally with a therapeutic dose of NAC.

Language of Publication

English

Unique Identifier

91114721

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MeSH Heading (Major)

Acetylcysteine|AD/*PD; Trace Elements|*PK

MeSH Heading

Administration, Oral; Adult; Calcium|PK; Copper|PK; Female; Human; Iron|PK; Magnesium|PK; Male; Middle Age; Zinc|PK

Publication Type

JOURNAL ARTICLE

ISSN

0031-6970

Country of Publication

GERMANY

CAS Registry/EC Number

0 (Trace Elements); 616-91-1 (Acetylcysteine); 7439-89-6 (Iron); 7439-95-4 (Magnesium); 7440-50-8 (Copper); 7440-66-6 (Zinc); 7440-70-2 (Calcium)

Record 9 from database: MEDLINE
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Title

The role of NAD(P)H:quinone oxidoreductase in quinone-mediated p21 induction in human colon carcinoma cells.

Author

Qiu XB; Cadenas E

Address

Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033, USA.

Source

Arch Biochem Biophys, 1997 Oct, 346:2, 241-51

Abstract

This study examines the role of NAD(P)H:quinone acceptor oxidoreductase (NQOR) (EC 1.6.99.2) in the metabolism of aziridinylbenzoquinones and the ensuing formation of reactive oxygen species in the induction of the cell cycle inhibitor p21 (WAF1, Cip1, or sdi1) in human colon carcinoma cells. The aziridinylbenzoquinones used were 2,5-diaziridinyl-1,4-benzoquinone (DZQ) and 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone (AZQ). The cell lines used in this study, BE and HT29 human colon carcinoma cell lines, are devoid of and overexpress NQOR activity, respectively. The rate of reduction of the above quinones in BE cells proceeded at similar rates (approximately 170 nmol/min/ mg protein) and, expectedly, it was not affected by the NQOR inhibitor, dicumarol. The metabolism of DZQ in HT29 cells was largely accomplished by NQOR (approximately 94%), whereas that of AZQ was accomplished by dicumarol-insensitive reductases. The metabolism of DZQ in HT29 cells was accompanied by H2O2 formation, which was approximately 10-fold higher than that ensuing from the activation of AZQ. In agreement with these data, the production of H2O2 during the activation of DZQ by purified NQOR was approximately 10-fold higher than that of AZQ. The formation of H2O2 during the metabolism of aziridinylbenzoquinones in BE cells was 24- to 57-fold lower than that in HT29 cells. At variance with HT29 cells, H2O2 formation by BE cells was insensitive to the catalase inhibitor sodium azide. The bioactivation of AZQ and DZQ in BE cells yielded O2.- and HO. as detected by spin trapping/EPR, the intensity of the former adduct being approximately 2-fold higher than that of the latter. These signals were insensitive to dicumarol. The metabolism of DZQ in HT29 cells yielded mainly HO. and a modest contribution of O2.- (ratio HO./O2.- approximately 10), whereas that of AZQ yielded a HO./O2.- approximately 2. The effect of dicumarol on the free radical pattern obtained during DZQ metabolism resulted in a strong inhibition (80%) of HO. production and a substantial increase of O2.- generation. The metabolism of DZQ and AZQ in BE cells was associated with a significant increase of p21 mRNA levels; the former quinone was approximately 2-fold more efficient than the latter. DZQ metabolism in HT29 cells led to an increase of p21 mRNA levels 15-fold higher than that observed with AZQ activation. Dicumarol did not inhibit p21 induction associated with the metabolism of DZQ in the NQOR-deficient BE cells, whereas the inhibitor decreased p21 induction in HT29 cells by approximately 30%. This modest inhibition is likely due to the low concentration of dicumarol used, which did not affect p21 constitutive levels in control experiments carried out in the absence of the quinone. p21 induction in HT29 cells was also inhibited by DTPA, a metal chelator, and N-acetylcysteine, a potent cellular anti-oxidant, suggesting that HO. may serve as an ultimate mediator for the induction. It may be surmised that the higher efficiency of DZQ in p21 induction may be related to its efficient metabolism by NQOR in HT29 cells and the associated high level of reactive oxygen species. The role of reactive oxygen species in p21 induction was further assessed upon supplementation of cells with H2O2:p21 induction in BE cells was 4-fold higher than that in HT29 cells. These findings suggest that assessment of the role of NQOR and reactive oxygen species in p21 induction requires careful consideration of the cell genotype.

Language of Publication

English

Unique Identifier

98001536

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MeSH Heading (Major)

Colonic Neoplasms|*EN; Cyclins|*BI/GE/PD; Gene Expression Regulation, Neoplastic|*GE; NAD(P)H Dehydrogenase (Quinone)|*ME; Quinones|*ME

MeSH Heading

Acetylcysteine|PD; Aziridines|ME; Benzoquinones|ME; Blotting, Northern; Cell Division|DE; Dicumarol|PD; DTPA|PD; Electron Spin Resonance Spectroscopy; Enzyme Inhibitors|PD; Human; Hydrogen Peroxide|ME; Hydroxyl Radical|ME; Kinetics; Molecular Structure; Reactive Oxygen Species|ME; RNA, Messenger|AN; Support, U.S. Gov't, P.H.S.; Tumor Cells, Cultured

Publication Type

JOURNAL ARTICLE

ISSN

0003-9861

Country of Publication

UNITED STATES

Record 10 from database: MEDLINE
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Title

Cytotoxicity of heavy metals in the human small intestinal epithelial cell line I-407: the role of glutathione.

Author

Keogh JP; Steffen B; Siegers CP

Address

Institute for Toxicology, Medical University of LÂubeck, Germany.

Source

J Toxicol Environ Health, 1994 Nov, 43:3, 351-9

Abstract

Cytotoxicities of metal salts were determined in the intestinal epithelial cell line I-407 in microwell culture plates over 48 h using the widely utilized and accepted neutral red uptake procedure. Rank order cytotoxicities induced by the metal salts (in terms of LC50 values) were found to be HgCl2 (32 microM) > CdCl2 (53 microM) > CuCl2 (156 microM) > T12SO4 (377 microM) > Pb(NO3)2 (1.99 mM). Combined administration of the two most toxic metals at their LC50's showed that their toxicities were not additive or synergistic. The role of glutathione in determining toxicity induced by the metal salts in these cells was assessed by inhibition of its synthesis. Buthionine sulfoximine pretreatment at 1 mM, which was not toxic to the cells, caused sustained reduction in cellular glutathione content (to 13.8% after 48 h) and increased toxicities induced by HgCl2 (5.7-fold) and CuCl2 (1.44-fold) as shown by reductions in the LC50 values. Toxicity induced by the other metals remained unaffected. Administration of glutathione with either HgCl2 or CdCl2 did not protect the cells against their toxicity, and in the case of cadmium its toxicity was exacerbated. N-Acetylcysteine diminished toxicity induced by mercury but not cadmium.

Language of Publication

English

Unique Identifier

95055873

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MeSH Heading (Major)

Glutathione|*PH; Intestine, Small|CY/*DE; Metals|*TO

MeSH Heading

Cadmium|TO; Cell Line; Chlorides|TO; Copper|TO; Epithelium|CY/DE; Human; Lead|TO; Mercuric Chloride|TO; Neutral Red; Nitrates|TO; Thallium|TO

Publication Type

JOURNAL ARTICLE

ISSN

0098-4108

Country of Publication

UNITED STATES

Record 11 from database: MEDLINE
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Title

The effects of various antioxidants on lipid peroxidation in stored whole blood.

Author

Knight JA; Searles DA

Address

Pathology and Laboratory Medicine Service, Salt Lake VA Medical Center.

Source

Ann Clin Lab Sci, 1994 Jul, 24:4, 294-301

Abstract

Since the introduction of acid-citrate-dextrose (ACD) in 1947 to anticoagulate and preserve whole blood for transfusion, various other improved nutrient formulas have been introduced that have significantly increased the viability and lifespan of stored erythrocytes. More recently, several studies involving lipid peroxidation have been reported in an attempt to understand alternative mechanisms that might lead to a further increase in red cell viability and extend the storage life of whole blood. In the current study, the effects of a variety of substances are reported whose antioxidant mechanisms differ; they include the transition metals manganese and zinc, the metal chelator phytic acid, and the free radical scavengers N-acetylcysteine, mannitol, uric acid, 1,3 dimethyluric acid, and quercetin. All but N-acetylcysteine, uric acid, and phytic acid were consistently effective in decreasing lipid peroxidation in stored red cells.

Language of Publication

English

Unique Identifier

95030929

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MeSH Heading (Major)

Antioxidants|*PD; Blood|*DE; Blood Preservation|*; Lipid Peroxides|*AI/BL

MeSH Heading

Chromatography, High Pressure Liquid; Human; Malondialdehyde|BL; Osmolar Concentration; Potassium|BL

Publication Type

JOURNAL ARTICLE

ISSN

0091-7370

Country of Publication

UNITED STATES

Record 12 from database: MEDLINE
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Title

Effects of phenelzine and hydralazine on hydrogen peroxide production and proteolysis in human red blood cells.

Author

Runge-Morris M; Novak RF

Address

Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan.

Source

J Pharmacol Exp Ther, 1993 Dec, 267:3, 1401-6

Abstract

The ability of the therapeutic agents phenelzine (PZ) and hydralazine (HD) to stimulate the rate of protein degradation and H2O2 production in human red blood cells (RBC) was characterized. PZ- and HD-stimulated proteolysis, as monitored either by a fluorescence assay or by high-pressure liquid chromatography, occurred in a dose-, time- and hematocrit-dependent manner. The more potent PZ (0.5 mM), in RBC suspension or hemolysate, stimulated the rate of leucine release by 131 and 63%, respectively, whereas HD (1.0 mM) in RBC suspension or hemolysate produced increases of 133 and 66% in the rate of leucine release, respectively. PZ (0.75 mM) addition to red cells resulted in a rapid stimulation of H2O2 generation during the first hour of incubation, whereas HD (0.75 mM) addition to red cells produced a gradual increase in the rate of H2O2 production over 5 h of incubation. Substantial inhibition of PZ- and HD-stimulated proteolysis in RBC was observed with N-acetylcysteine, N-ethylmaleimide and the inhibitors of methemoglobin reduction, NADP and 2'AMP. In contrast, antioxidants dithiothreitol, dimethylthiourea, dimethyl sulfoxide and dimethylfuran had little effect on the rates of PZ- and HD-stimulated protein degradation. Western blot analysis demonstrated little change in the membrane-bound levels of the calcium-activated neutral protease calpain after incubation with PZ or HD. However, PZ- and HD-stimulated amino acid release was inhibited (approximately 30-50%) by the calcium chelator EGTA, suggesting a potential role for calcium-activated neutral protease and divalent metal cations in PZ- and HD-stimulated proteolysis.

Language of Publication

English

Unique Identifier

94087597

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MeSH Heading (Major)

Blood Proteins|*ME; Erythrocytes|*DE/EN/*ME; Hydralazine|*PD; Hydrogen Peroxide|*BL; Phenelzine|*PD

MeSH Heading

Blotting, Western; Calpain|BL; Cells, Cultured; Chromatography, High Pressure Liquid; Egtazic Acid|PD; Free Radical Scavengers; Human; Reactive Oxygen Species|PD; Stimulation, Chemical; Support, U.S. Gov't, P.H.S.

Publication Type

JOURNAL ARTICLE

ISSN

0022-3565

Country of Publication

UNITED STATES

CAS Registry/EC Number

EC 3.4.22.17 (Calpain); 0 (Blood Proteins); 0 (Free Radical Scavengers); 0 (Reactive Oxygen Species); 51-71-8 (Phenelzine); 67-42-5 (Egtazic Acid); 7722-84-1 (Hydrogen Peroxide); 86-54-4 (Hydralazine)

Record 13 from database: MEDLINE
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Title

Differential effects of organic hydroperoxides and hydrogen peroxide on proteolysis in human erythrocytes.

Author

Runge-Morris M; Frank P; Novak RF

Address

Department of Pharmacology, Northwestern University Medical and Dental Schools, Chicago, Illinois 60611.

Source

Chem Res Toxicol, 1989 Mar-Apr, 2:2, 76-83

Abstract

The effects of tert-butyl hydroperoxide, cumene hydroperoxide, and hydrogen peroxide on proteolysis in human red blood cells have been examined. The organic hydroperoxides effectively stimulated the rate of protein degradation in red cells and in hemolysate; in contrast, H2O2 addition was without significant effect in either system. tert-Butyl hydroperoxide or cumene hydroperoxide (8 mM) increased the rate of protein degradation in red cells 2.3- and 4-fold, respectively, relative to control as monitored by tyrosine release. In hemolysate, tert-butyl hydroperoxide and cumene hydroperoxide, present at 8 mM, produced a 2- and 3-fold increase in the rate of protein degradation, respectively, as compared to controls. Hydroperoxide-stimulated proteolysis in red cells or in hemolysate was concentration-dependent and reached saturation at 8 mM hydroperoxide. The reaction was linear for 2 h after which a plateau was reached. In contrast to the results observed for the organic hydroperoxides, H2O2 (100 or 200 mM) addition either alone or in the presence of the catalase inhibitor 3-amino-1,2,4-triazole (50-200 mM), failed to stimulate proteolysis. N-Acetylcysteine (20 mM) and dimethylthiourea (50 mM) inhibited the rate of hydroperoxide-stimulated proteolysis in red cells by approximately 50 and approximately 35%, respectively, and in hemolysate by 25 and 40%, respectively. The hydroxyl radical scavengers methyl sulfoxide (50 mM) or dimethylfuran (50 mM), metal ion chelators, or spin traps failed to decrease significantly the rate of organic hydroperoxide stimulated proteolysis. In addition, inhibitors of the calpain/procalpain system in red cell or hemolysate incubations challenged by organic hydroperoxide were without significant effect on the rate of proteolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Language of Publication

English

Unique Identifier

92119078

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MeSH Heading (Major)

Benzene Derivatives|*PD; Blood Proteins|*ME; Erythrocytes|*ME; Hydrogen Peroxide|*PD; Peroxides|*PD

MeSH Heading

Amino Acids|BL; Amitrole|PD; Antioxidants|PD; Chelating Agents|PD; Chromatography, High Pressure Liquid; Fluorescence; Human; Hydrolysis; In Vitro; Protease Inhibitors|PD; Support, U.S. Gov't, P.H.S.; Tyrosine|ME

Publication Type

JOURNAL ARTICLE

ISSN

0893-228X

Country of Publication

UNITED STATES

CAS Registry/EC Number

0 (Amino Acids); 0 (Antioxidants); 0 (Benzene Derivatives); 0 (Blood Proteins); 0 (Chelating Agents); 0 (Peroxides); 0 (Protease Inhibitors); 55520-40-6 (Tyrosine); 61-82-5 (Amitrole); 75-91-2 (tert-butylhydroperoxide); 7722-84-1 (Hydrogen Peroxide); 80-15-9 (cumene hydroperoxide)

Record 14 from database: MEDLINE
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Title

Oxygen tension regulates heme oxygenase-1 gene expression in mammalian cell lines.

Author

Takahashi S; Takahashi Y; Yoshimi T; Miura T

Address

School of Life Science, Tokyo University of Pharmacy and Life Science, Japan.

Source

Cell Biochem Funct, 1998 Sep, 16:3, 183-93

Abstract

The gene expression of heme oxygenase-1 (HO-1) was studied in mammalian cell lines exposed to hyperoxia. Northern blot analysis demonstrated that hyperoxic exposure increased the HO-1 mRNA levels in various types of cells, including human hepatoma (HepG2) cells. This increase was time- and dose-dependent, and reversible. The HO-1 mRNA levels in HepG2 cells were increased to 2.3- and 4.2-fold of the control by hyperoxic exposure of 6 and 23 h, respectively. Cycloheximide and actinomycin D inhibited the increases in the HO-1 mRNA level produced by hyperoxia, indicating that response to hyperoxia is dependent on de novo protein synthesis and mRNA transcription. Antioxidants, desferrioxamine (DES) and o-phenanthroline (OP) partially inhibited the HO-1 mRNA elevation by hyperoxia. In addition to hyperoxia, sodium arsenite (NaAsO2), cadmium chloride (CdCl(2)) and hydrogen peroxide (H2O2), which are reactive oxygen intermediates (ROI) generators, increased the HO-1 mRNA level by 11-, 22- and 2.5-fold, respectively. OP, an antioxidant and a bivalent metal chelator, blocked the HO-1 mRNA elevation induced either by hyperoxia or by the three ROI generators. In contrast to OP, N-acetylcysteine (NAC), an antioxidant and membrane-permeable reducing reagent, enhanced the HO-1 mRNA elevation induced by hyperoxia, although NAC inhibited the mRNA elevation induced by NaAsO2, CdCl2 and H2O2. These results indicate that oxygen tension regulates HO-1 gene expression and suggest that hyperoxia-specific and redox-sensitive regulators may be involved in hyperoxia-mediated HO-1 gene expression.

Language of Publication

English

Unique Identifier

98419647

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MeSH Heading (Major)

Gene Expression Regulation, Enzymologic|*; Heme Oxygenase (Decyclizing)|*BI/GE; Oxygen|*PD

MeSH Heading

Animal; Antioxidants|PD; Cell Line; Cell Survival; Cycloheximide|PD; Dactinomycin|PD; Dose-Response Relationship, Drug; Human; Mice; Nucleic Acid Synthesis Inhibitors|PD; Oxidants|PD; Protein Synthesis Inhibitors|PD; Rats; RNA, Messenger|AN; Support, Non-U.S. Gov't

Publication Type

JOURNAL ARTICLE

ISSN

0263-6484

Country of Publication

ENGLAND

CAS Registry/EC Number

EC 1.14.99.- (heme oxygenase-1); EC 1.14.99.3 (Heme Oxygenase (Decyclizing)); 0 (Antioxidants); 0 (Nucleic Acid Synthesis Inhibitors); 0 (Oxidants); 0 (Protein Synthesis Inhibitors); 0 (RNA, Messenger); 50-76-0 (Dactinomycin); 66-81-9 (Cycloheximide); 7782-44-7 (Oxygen)

Record 15 from database: MEDLINE
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Title

Chemoprotectants for cancer chemotherapy.

Author

Dorr RT

Address

Department of Medicine, University of Arizona Medical School, Tucson.

Source

Semin Oncol, 1991 Feb, 18:1 Suppl 2, 48-58

Abstract

Maximal dosing of cytotoxic chemotherapy drugs is often limited by the development of severe nonmyelosuppressive toxicities. Numerous studies have demonstrated that sulfur-containing nucleophiles can antagonize the dose-limiting effects of alkylating agents on the genitourinary tract. Examples include the use of sodium thiosulfate to prevent cisplatin-induced renal tubular necrosis and the use of sulfhydryl-containing compounds like N-acetylcysteine and 2-mercaptoethanesulfonate (mesna) to block oxazophosphorine-induced bladder toxicity. Mesna does not block the antitumor action of oxazophosphorines due to its rapid formation of the inactive dimer dimesna in the bloodstream. The active monomer is selectively reduced from dimesna in renal tubule cells, thereby limiting the inactivation of toxins like acrolein to the genitourinary tract. Recent clinical trials suggest that oral mesna has adequate bioavailability (roughly 50% by urinary thiol measurements) to prevent urotoxicity in high-dose ifosfamide regimens. In addition, mesna is stable in aqueous oral formulations. This may facilitate more convenient oral mesna dosing in protocols using high-dose cyclophosphamide or ifosfamide. Whereas agents like mesna and sodium thiosulfate complex directly with activated (electrophilic) alkylator species, chemoprotectants for the anthracyclines appear to complex with metal cofactors like iron, which are required for the production of cardiotoxicity. Several ethylenediaminetetraacetic-lik e agents have been evaluated, and a water-soluble piperazinyl derivative, ICRF-187, is currently undergoing clinical evaluation in patients receiving large cumulative doxorubicin doses. An initial clinical trial suggests that ICRF-187 can prevent doxorubicin-induced cardiomyopathy. As with mesna, ICRF-187 does not block the myelosuppressive or the antitumor effects of doxorubicin. Overall, these studies show that site-selective chemoprotection is now feasible for at least two major classes of anticancer agents.

Language of Publication

English

Unique Identifier

91126523

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MeSH Heading (Major)

Antineoplastic Agents|*AE; Neoplasms|*DT

MeSH Heading

Antibiotics, Anthracycline|AE; Asparaginase|PD; Cisplatin|AE; Cyclophosphamide|AE; Fluorouracil|AE; Human; Ifosfamide|AE; Leucovorin|PD; Mesna|PD; Methotrexate|AE; Razoxane|PD; Sulfhydryl Compounds|PD; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Uridine|PD

Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0093-7754

Country of Publication

UNITED STATES

CAS Registry/EC Number

EC 3.5.1.1 (Asparaginase); 0 (Antibiotics, Anthracycline); 0 (Antineoplastic Agents); 0 (Sulfhydryl Compounds); 15663-27-1 (Cisplatin); 21416-87-5 (Razoxane); 3778-73-2 (Ifosfamide); 50-18-0 (Cyclophosphamide); 51-21-8 (Fluorouracil); 58-05-9 (Leucovorin); 58-96-8 (Uridine); 59-05-2 (Methotrexate)

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