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

Authors
Modriansky-M; Tyurina-YY; Tyurin-VA; Matsura-T; Shvedova-AA; Yalowich-JC; Kagan-VE
Source
Toxicology 2002 Aug; 177(1):105-117
NIOSHTIC No.
20023498
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.
Keywords
Phenolic-compounds; Phenols; Antioxidants; Metabolites; Lipid-peroxidation; Lipids; Laboratory-animals; Animal-studies; Animals; Liver-damage; Oxidation
Contact
Department of Environmental and Occupational Health, University of Pittsburgh, FORBL Room 234, 3343 Forbes Avenue, Pittsburgh, PA 15260, USA
CODEN
TXCYAC
CAS No.
7722-84-1; 70-18-8; 64-86-8; 50-81-7
Publication Date
20020801
Document Type
Journal Article
Email Address
oregon@tunw.upol.cz
Fiscal Year
2002
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
0300-483X
NIOSH Division
HELD
Priority Area
Disease and Injury: Allergic and Irritant Dermatitis
Source Name
Toxicology
State
PA; WV
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