Tags

Type your tag names separated by a space and hit enter

Anti-/pro-oxidant effects of phenolic compounds in cells: are colchicine metabolites chain-breaking antioxidants?

Abstract

Effective scavenging of reactive radicals and low reactivity of generated secondary antioxidant radicals towards vital intracellular components are two critical requirements for a chain-breaking antioxidant. Tubulin-binding properties aside, colchicine metabolites remain largely untested for other possible biological activities, including antioxidant activity. Mourelle et al. [Life Sci. 45 (1989) 891] proposed that colchiceine (EIN) acts as an antioxidant and protective agent against lipid peroxidation in a rat model of liver injury. Since EIN as well as two other colchicine metabolites, 2-demethylcolchicine (2DM) and 3-demethylcolchicine (3DM), possess a hydroxy-group on their carbon ring that could participate in radical scavenging, we tested whether they can act as chain-breaking antioxidants. Using our fluorescence-HPLC assay with metabolically incorporated oxidation-sensitive cis-parinaric acid (PnA) we studied the effects of colchicine metabolites on peroxidation of different classes of membrane phospholipids in HL-60 cells. None of the colchicine metabolites in concentrations ranging from 10(-6) to 10(-4) M was able to protect phospholipids against peroxidation induced by either azo-initiators of peroxyl radicals or via myeloperoxidase (MPO)-catalyzed reactions in the presence of hydrogen peroxide. However, the metabolites did exhibit dose-dependent depletion of glutathione, resembling the behavior of etoposide, a hindered phenol with antioxidant properties against lipid peroxidation. Electron spin resonance (ESR) experiments demonstrated that in a catalytic system containing horseradish peroxidase (HRP)/H(2)O(2), colchicine metabolites undergo one-electron oxidation to form phenoxyl radicals that, in turn, cause ESR-detectable ascorbate radicals by oxidation of ascorbate. Phenoxyl radicals of colchicine metabolites formed through MPO-catalyzed H(2)O(2)-dependent reactions in HL-60 cells and via HRP/H(2)O(2) in model systems can also oxidize GSH. Thus, colchicine metabolites possess the prerequisites of many antioxidants, i.e. a nucleophilic hydroxy-group on a carbon ring and the ability to scavenge reactive radicals and form a secondary radical. However, the latter retain high reactivity towards critical biomolecules in cells such as lipids, thiols, ascorbate, thereby, rendering colchicine metabolites effective radical scavengers but not effective chain-breaking antioxidants.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Environmental and Occupational Health, University of Pittsburgh, FORBL Room 234, 3343 Forbes Avenue, Pittsburgh, PA 15260, USA. oregon@tunw.upol.cz

    , , , , ,

    Source

    Toxicology 177:1 2002 Aug 01 pg 105-17

    MeSH

    Antioxidants
    Ascorbic Acid
    Chromatography, High Pressure Liquid
    Colchicine
    Dose-Response Relationship, Drug
    Electron Spin Resonance Spectroscopy
    Fatty Acids, Unsaturated
    Fluorescent Dyes
    Free Radical Scavengers
    Glutathione
    HL-60 Cells
    Humans
    Lipid Peroxidation
    Membrane Lipids
    Phospholipids
    Reactive Oxygen Species

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    12126799

    Citation

    Modriansky, Martin, et al. "Anti-/pro-oxidant Effects of Phenolic Compounds in Cells: Are Colchicine Metabolites Chain-breaking Antioxidants?" Toxicology, vol. 177, no. 1, 2002, pp. 105-17.
    Modriansky M, Tyurina YY, Tyurin VA, et al. Anti-/pro-oxidant effects of phenolic compounds in cells: are colchicine metabolites chain-breaking antioxidants? Toxicology. 2002;177(1):105-17.
    Modriansky, M., Tyurina, Y. Y., Tyurin, V. A., Matsura, T., Shvedova, A. A., Yalowich, J. C., & Kagan, V. E. (2002). Anti-/pro-oxidant effects of phenolic compounds in cells: are colchicine metabolites chain-breaking antioxidants? Toxicology, 177(1), pp. 105-17.
    Modriansky M, et al. Anti-/pro-oxidant Effects of Phenolic Compounds in Cells: Are Colchicine Metabolites Chain-breaking Antioxidants. Toxicology. 2002 Aug 1;177(1):105-17. PubMed PMID: 12126799.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Anti-/pro-oxidant effects of phenolic compounds in cells: are colchicine metabolites chain-breaking antioxidants? AU - Modriansky,Martin, AU - Tyurina,Yulia Y, AU - Tyurin,Vladimir A, AU - Matsura,Tatsuya, AU - Shvedova,Anna A, AU - Yalowich,Jack C, AU - Kagan,Valerian E, PY - 2002/7/20/pubmed PY - 2002/9/6/medline PY - 2002/7/20/entrez SP - 105 EP - 17 JF - Toxicology JO - Toxicology VL - 177 IS - 1 N2 - Effective scavenging of reactive radicals and low reactivity of generated secondary antioxidant radicals towards vital intracellular components are two critical requirements for a chain-breaking antioxidant. Tubulin-binding properties aside, colchicine metabolites remain largely untested for other possible biological activities, including antioxidant activity. Mourelle et al. [Life Sci. 45 (1989) 891] proposed that colchiceine (EIN) acts as an antioxidant and protective agent against lipid peroxidation in a rat model of liver injury. Since EIN as well as two other colchicine metabolites, 2-demethylcolchicine (2DM) and 3-demethylcolchicine (3DM), possess a hydroxy-group on their carbon ring that could participate in radical scavenging, we tested whether they can act as chain-breaking antioxidants. Using our fluorescence-HPLC assay with metabolically incorporated oxidation-sensitive cis-parinaric acid (PnA) we studied the effects of colchicine metabolites on peroxidation of different classes of membrane phospholipids in HL-60 cells. None of the colchicine metabolites in concentrations ranging from 10(-6) to 10(-4) M was able to protect phospholipids against peroxidation induced by either azo-initiators of peroxyl radicals or via myeloperoxidase (MPO)-catalyzed reactions in the presence of hydrogen peroxide. However, the metabolites did exhibit dose-dependent depletion of glutathione, resembling the behavior of etoposide, a hindered phenol with antioxidant properties against lipid peroxidation. Electron spin resonance (ESR) experiments demonstrated that in a catalytic system containing horseradish peroxidase (HRP)/H(2)O(2), colchicine metabolites undergo one-electron oxidation to form phenoxyl radicals that, in turn, cause ESR-detectable ascorbate radicals by oxidation of ascorbate. Phenoxyl radicals of colchicine metabolites formed through MPO-catalyzed H(2)O(2)-dependent reactions in HL-60 cells and via HRP/H(2)O(2) in model systems can also oxidize GSH. Thus, colchicine metabolites possess the prerequisites of many antioxidants, i.e. a nucleophilic hydroxy-group on a carbon ring and the ability to scavenge reactive radicals and form a secondary radical. However, the latter retain high reactivity towards critical biomolecules in cells such as lipids, thiols, ascorbate, thereby, rendering colchicine metabolites effective radical scavengers but not effective chain-breaking antioxidants. SN - 0300-483X UR - https://www.unboundmedicine.com/medline/citation/12126799/Anti_/pro_oxidant_effects_of_phenolic_compounds_in_cells:_are_colchicine_metabolites_chain_breaking_antioxidants L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300483X02001993 DB - PRIME DP - Unbound Medicine ER -