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OtherTOXICOLOGY

Calcium-Dependent Mitochondrial Formation of Species Mediating DNA Single Strand Breakage in U937 Cells Exposed to Sublethal Concentrations of Tert-Butylhydroperoxide

Andrea Guidarelli, Emilio Clementi, Clara Sciorati, Flaminio Cattabeni and Orazio Cantoni
Journal of Pharmacology and Experimental Therapeutics October 1997, 283 (1) 66-74;
Andrea Guidarelli
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Emilio Clementi
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Clara Sciorati
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Flaminio Cattabeni
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Orazio Cantoni
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Abstract

Treatment of U937 cells with a sublethal albeit DNA-damaging concentration of tert-butylhydroperoxide (tB-OOH) enhanced mitochondrial Ca++ uptake and ruthenium red (RR), a polycation that inhibits the calcium uniporter of mitochondria, significantly reduced the extent of DNA cleavage generated by the hydroperoxide. Release of Ca++ from the ryanodine(Ry)/caffeine(Cf)-sensitive stores further increased mitochondrial Ca++ uptake and elicited a parallel enhancement in DNA strand scission induced by tB-OOH that was prevented by both Ry and RR. DNA damage caused by tB-OOH alone or associated with either Cf or RR was prevented by iron chelators, insensitive to antioxidants and repaired with kinetics superimposable with those observed after treatment with H2O2. Cf enhanced the DNA-damaging effects of tB-OOH in permeabilized cells as well, and similar effects were observed upon addition of CaCl2. Cf did not further increase the formation of DNA lesions elicited by tB-OOH in the presence of CaCl2. The enhancing effects of Cf were prevented by RR and ryanodine, whereas those mediated by exogenous calcium were prevented only by RR. DNA strand scission caused by tB-OOH alone or associated with Cf in the permeabilized cell system was severely inhibited by ethylene glycol-bis(β-aminoethyl ether)-N, N,N′,N′-tetraacetic acid. The mechanism(s) whereby Ca++promotes the mitochondrial formation of species that will ultimately result in the formation of DNA lesions was subsequently analyzed using intact as well as permeabilized cells. Hydrogen peroxide was identified to be one of these species.

Footnotes

  • Send reprint requests to: Dr. Orazio Cantoni, Istituto di Farmacologia e Farmacognosia, Università di Urbino, Via S. Chiara, 27, 61029 Urbino (PS), Italy.

  • Abbreviations:
    SSBs
    DNA single strand breaks
    tB-OOH
    tert-butylhydroperoxide
    EGTA
    ethylene glycol-bis(β-aminoethyl ether)-N, N,N′,N′-tetraacetic acid
    Tg
    thapsigargin
    Iono
    ionomycin
    Cf
    caffeine
    FCCP
    carbonyl cyanidep-(trifluoromethoxy)phenylhydrazone
    RR
    ruthenium red
    Ry
    ryanodine
    SOD
    superoxide dismutase, BHT, butylated hydroxytoluene
    DPPD
    N, N′-diphenyl-1,4-phenylene-diamine
    o-pt
    o-phenanthroline
    EDTA
    etylenediaminetetraacetic acid
    [Ca++]i
    intracellular free Ca++ concentration
    SERCA
    sarcoplasmic/endoplasmic reticulum Ca++- ATPase
    IP3
    inositol 1, 4, 5-trisphosphate
    ER
    endoplasmic reticulum
    • Received March 4, 1997.
    • Accepted June 23, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 1
1 Oct 1997
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OtherTOXICOLOGY

Calcium-Dependent Mitochondrial Formation of Species Mediating DNA Single Strand Breakage in U937 Cells Exposed to Sublethal Concentrations of Tert-Butylhydroperoxide

Andrea Guidarelli, Emilio Clementi, Clara Sciorati, Flaminio Cattabeni and Orazio Cantoni
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 66-74;

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OtherTOXICOLOGY

Calcium-Dependent Mitochondrial Formation of Species Mediating DNA Single Strand Breakage in U937 Cells Exposed to Sublethal Concentrations of Tert-Butylhydroperoxide

Andrea Guidarelli, Emilio Clementi, Clara Sciorati, Flaminio Cattabeni and Orazio Cantoni
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 66-74;
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