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OtherTOXICOLOGY

The Role of Thiols in Protecting against Simultaneous Toxicity of Menadione to Platelet Plasma and Intracellular Membranes

Youn-Sook Cho, Mee-Jeong Kim, Joo-Young Lee and Jin-Ho Chung
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1335-1340;
Youn-Sook Cho
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Mee-Jeong Kim
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Joo-Young Lee
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Jin-Ho Chung
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Abstract

Our previous study suggested that menadione (MEN) is cytotoxic to platelets of rats due to oxidative stress. To elucidate the mechanism of this toxicity, MEN-induced depletion of total cellular thiols or depletion of gutathione was studied in intact rat platelets. Treatment with MEN resulted in dose and time dependent damage to plasma (assessed by lactate dehydrogenase leakage) and intracellular (assessed by serotonin release) membranes. These events were well correlated with total cellular thiol depletion by MEN treatment, however MEN-induced glutathione depletion occurred rapidly and before plasma and intracellular membrane damage. Unlike hepatocytes, oxidized glutathione was not formed, suggesting that protein arylation, rather than oxidative stress, might be the ultimate mechanism for MEN cytotoxicity in platelets. Platelets were pretreated with dithiothreitol to supplement the total cellular thiol pool or with 1-chloro-2,4-dinitrobenzene to deplete glutathione, a soluble thiol. Dithiothreitol pretreatment to platelets protected against MEN-induced toxicity to both plasma membranes (prevented lactate dehydrogenase leakage and changes in platelet turbidity) and intracellular membranes (prevented serotonin release), although 1-chloro-2,4-dinitrobenzene pretreatment potentiated these toxicities. These results indicate that the total cellular pool of thiols plays a vital role in maintaining plasma and intracellular membrane integrity.

Footnotes

  • Send reprint requests to: Dr. Jin-Ho Chung, College of Pharmacy, Seoul National University, Shinrim-dong San 56–1, Seoul 151–742 Korea

  • ↵1 Study was supported by a grant from Research Center for New Drug Developments (KOSEF-RCNDD).

  • Abbreviations:
    PRP
    platelet-rich plasma
    PPP
    platelet-poor plasma
    MEN
    menadione
    MEN-SG
    menadione glutathione conjugate
    CDNB
    1-chloro-2,4-dinitrobenzene
    DTNB
    5,5′-dithiobis(2-nitrobenzoic acid)
    TCA
    trichloroacetic acid
    LDH
    lactate dehydrogenase
    GSH
    glutathione
    GSSG
    oxidized glutathione
    DTT
    dithiothreitol
    DMSO
    dimethyl sulfoxide
    DMNQ
    2,3-dimethoxy-1,4-naphthoquinone
    NADH
    nicotinamide adenine dinucleotide
    NADPH
    nicotinamide adenine dinucleotide phosphate
    MOPS
    3-(N-morpholino)propanesulfonic acid
    • Received July 8, 1996.
    • Accepted November 25, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherTOXICOLOGY

The Role of Thiols in Protecting against Simultaneous Toxicity of Menadione to Platelet Plasma and Intracellular Membranes

Youn-Sook Cho, Mee-Jeong Kim, Joo-Young Lee and Jin-Ho Chung
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1335-1340;

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OtherTOXICOLOGY

The Role of Thiols in Protecting against Simultaneous Toxicity of Menadione to Platelet Plasma and Intracellular Membranes

Youn-Sook Cho, Mee-Jeong Kim, Joo-Young Lee and Jin-Ho Chung
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1335-1340;
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