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Research ArticleTOXICOLOGY

O 2-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Againstd-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays

Jie Liu, Joseph E. Saavedra, Tong Lu, Jian-Guo Song, James Clark, Michael P. Waalkes and Larry K. Keefer
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 18-25; DOI: https://doi.org/10.1124/jpet.300.1.18
Jie Liu
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Joseph E. Saavedra
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Tong Lu
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Jian-Guo Song
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James Clark
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Michael P. Waalkes
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Larry K. Keefer
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Abstract

O 2-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), a liver-selective nitric oxide (NO)-donating prodrug, is metabolized by hepatic enzymes to release NO within the liver. This study was undertaken to examine the effects of V-PYRRO/NO ond-galactosamine/lipopolysaccharide (GlaN/LPS)-induced liver injury in mice. Mice were given injections of V-PYRRO/NO (10 mg/kg, s.c. at 2-h intervals) before and after GlaN/LPS (700 mg/30 μg/kg, i.p.). V-PYRRO/NO administration dramatically reduced GlaN/LPS-induced hepatotoxicity, as evidenced by reduced serum alanine aminotransferase activity and improved pathology. To examine the mechanisms of the protection, cDNA microarray was performed to profile the gene expression pattern in livers of mice treated with GlaN/LPS, GlaN/LPS plus V-PYRRO/NO, or controls. V-PYRRO/NO administration greatly ameliorated GlaN/LPS-induced alterations in the expression of genes encoding the stress response, DNA damage/repair response, and drug-metabolizing enzymes in accordance with hepatoprotection. Gel shift assay and Western blot analysis supported microarray results, showing that V-PYRRO/NO suppressed GlaN/LPS-induced activation of nuclear factor-κB and GlaN/LPS-induced increases in caspase-1, caspase-8, tumor necrosis factor receptor 1 (TNFR1)-associated death domain, and TNF-related apoptosis-inducing ligand. Immunohistochemical analysis further revealed that GlaN/LPS-induced activation of TNFR1, caspase-3, and hepatocellular apoptosis was ameliorated by V-PYRRO/NO treatment. GlaN/LPS-induced elevation of hepatic caspase-3 activity was diminished by V-PYRRO/NO treatment. In addition, V-PYRRO/NO alone suppressed the basal expression of genes encoding inducible NO synthase and TNF-α-related components, as revealed by mouse 1.2 array. In summary, this study demonstrates that the liver-selective NO donor, V-PYRRO/NO, is effective in blocking GlaN/LPS-induced hepatotoxicity in mice, and that this protection appears to involve, at least in part, the suppression of the TNF-α-mediated cell death pathways.

Footnotes

  • This project has been funded in part by the National Cancer Institute/National Institutes of Health under Contract NO1-CO-56000.

  • Abbreviations

    V-PYRRO/NO
    O 2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
    NO
    nitric oxide
    LPS
    lipopolysaccharide
    GlaN/LPS
    galactosamine plus LPS
    ALT
    alanine aminotransferase
    TNF-α
    tumor necrosis factor-α
    TNFR
    tumor necrosis factor receptor
    NF-κB
    nuclear factor-κB
    TRADD
    TNFR1-associated death domain
    TRAIL
    TNF-related apoptosis inducing ligand
    TBST
    Tris-buffered saline/Tween 20
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling G3PDH, glyceraldehyde-3-phosphate dehydrogenase
    • Received June 29, 2001.
    • Accepted September 7, 2001.
    • U.S. Government
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
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    1 Jan 2002
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    Research ArticleTOXICOLOGY

    O 2-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Againstd-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays

    Jie Liu, Joseph E. Saavedra, Tong Lu, Jian-Guo Song, James Clark, Michael P. Waalkes and Larry K. Keefer
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 18-25; DOI: https://doi.org/10.1124/jpet.300.1.18

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    Research ArticleTOXICOLOGY

    O 2-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Againstd-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays

    Jie Liu, Joseph E. Saavedra, Tong Lu, Jian-Guo Song, James Clark, Michael P. Waalkes and Larry K. Keefer
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 18-25; DOI: https://doi.org/10.1124/jpet.300.1.18
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