Skip NavigationSkip to Content
Return Return to Search Results

The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice

  1. Author:
    Liu, J.
    Li, C. X.
    Waalkes, M. P.
    Clark, J.
    Myers, P.
    Saavedra, J. E.
    Keefer, L. K.

  2. Author Address

    NIEHS, Inorgan Carcinogensis Sect, Lab Comparat Carcinogenesis, NCI, Mail Drop F0-09, Res Triangle Pk, NC 27709 USA NIEHS, Inorgan Carcinogensis Sect, Lab Comparat Carcinogenesis, NCI, Res Triangle Pk, NC 27709 USA NIEHS, Comparat Med Branch, Res Triangle Pk, NC USA NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD USA Liu J NIEHS, Inorgan Carcinogensis Sect, Lab Comparat Carcinogenesis, NCI, Mail Drop F0-09, Res Triangle Pk, NC 27709 USA
    1. Year: 2003
  2. Journal: Hepatology
    1. 37
    2. 2
    3. Pages: 324-333
  4. Type of Article: Article
  1. Abstract:

    The liver-selective nitric oxide (NO) donor, O-2-vinyl 1- (pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V PYRRO/NO), is metabolized by P-450 enzymes to release NO in the liver, and is shown to protect the liver from tumor necrosis factor a (TNF- alpha)-induced apoptosis and D-glactosamine/endotoxin-induced hepatotoxicity. This study was undertaken to examine the effects of V PYRRO/NO on acetaminophen-induced hepatotoxicity in mice. Mice were given V PYRRO/NO via osmotic pumps (1.8-5.4 mg/ml,, 8 muL/h) 4 to 16 hours before a hepatotoxic dose of acetaminophen (600 mg/kg, intraperitoneally [ip]). V PYRRO/NO administration dramatically reduced acetaminophen-induced hepatotoxicity in a dose- and time-dependent manner, as evidenced by reduced serum alanine aminotransferase (ALT) activity, reduced hepatic congestion, apoptosis, and improved hepatocellular pathology. The protection afforded by V PYRRO/NO does not appear to be caused by a decrease in the formation of toxic acetaminophen metabolites, which consumes glutathione (GSH), because V PYRRO/NO did not alter acetaminophen-induced hepatic GSH depletion. Acetaminophen-induced lipid peroxidation, as determined by the concentrations of 4- hydroxyalkenals (4-HNE) and malondialdehyde (MDA), was reduced significantly by V PYRRO/NO treatment. Although pretreatment was most effective, administration of V PYRRO/NO simultaneously with acetaminophen also was able to reduce acetaminophen hepatotoxicity. Genomic analysis of the liver samples 10 hours after acetaminophen intoxication showed the enhanced expression of genes associated with stress/oxidative stress, apoptosis/cell death, and DNA damage/repair. Acetaminophen- induced alterations in gene expression were attenuated significantly by V PYRRO/NO. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western-blot analysis confirmed microarray results. In conclusion, V PYRRO/NO is effective in blocking acetaminophen -induced hepatotoxicity in mice. This protection may involve the reduction of oxidative stress, the inhibition of apoptosis, and possibly the maintenance of hepatic vasculature to prevent congestion.

    See More

  1. Keywords:

External Sources

  1. No sources found.

Library Notes

  1. No notes added.
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel