Nitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice

Akahori, Michiya; Yamada, Shinji; Takeyama, Naoshi; Tanaka, Takaya

doi:10.1006/jsre.1999.5621

Cited by 13 publications

(7 citation statements)

References 32 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This effect was reported in two studies with MrkA as well (Meneses-Lorente et al, 2004;Mortishire-Smith et al, 2004). We did not find literature to support effects of actinomycin D on mitochondrial β-oxidation or hepatic steatosis (Akahori et al, 1999;Bader et al, 1974;Czauderna et al 2000;Goldblatt et al, 1969;Kleeberg et al, 1979;Kuehl, 1969;McGeachin et al, 1978). Thus, the basis for the transcriptional similarity of MrkA to these compounds does not appear to center on mitochondrial effects.…”

Section: Discussioncontrasting

confidence: 36%

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

Cornwell

Ulrich²

2007

Toxicol Pathol

View full text Add to dashboard Cite

A compendium of hepatic gene expression signatures was used to identify a mechanistic basis for the hepatic toxicity of an experimental CCR5 antagonist (MrkA). Development of MrkA, a potential HIV therapeutic, was discontinued due to hepatotoxicity in preclinical studies. Rats were treated with MrkA at 3 dose levels (50, 250, and 500 mg/kg) for 1, 3, or 7 days. Hepatic toxicity (vacuolation, consistent with steatosis, and elevated serum transaminase levels) was observed at 250 and 500 mg/kg, but not at 50 mg/kg. Hepatic gene expression profiles were compared to a compendium of hepatic expression profiles. MrkA was similar to 3 beta-oxidation inhibitors (valproate, cyclopropane carboxylate, pivalate), 8 PPARalpha agonists (fenofibrate, bezafibrate and 6 fibrate analogues), and 3 other diverse compounds (diethylnitrosamine, microcystin LR & actinomycin D). These data indicate MrkA to be a mitochondrial inhibitor, and activation of PPARalpha-regulated transcription was thought to be due to an accumulation of endogenous ligands. While mitochondrial inhibition was likely responsible for steatosis, canonical pathway analysis revealed that progression to liver injury may be mediated by activation of the innate immune system primarily through NF-kB pathways. These results demonstrate the utility of a gene expression response compendium in developing transcriptional biomarkers and identifying the mechanistic basis for toxicity.

show abstract

Section: Discussioncontrasting

confidence: 36%

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

Cornwell

Ulrich²

2007

Toxicol Pathol

View full text Add to dashboard Cite

show abstract

“…Importantly, all these alterations in gene expression were greatly ameliorated by V-PYRRO/NO treatment, consistent with the observed hepatoprotection. It has been shown recently that suppression of endogenous NO production by inducible NO synthase inhibitors aggravates LPS-induced hepatic injury, resulting in the formation of oxidative DNA damage (Akahori et al, 1999;Takemura et al, 2000), whereas administration of NO donors, such as hydroxylamine, increased plasma nitrite/nitrate level and ameliorated actinomycin D/LPS-induced liver DNA fragmentation (Akahori et al, 1999). Thus, our gene array study provided a profile of genetic events associated with GlaN/LPS-induced hepatotoxicity, and a clue toward the mechanisms of V-PYRRO/NO protection.…”

Section: Discussionmentioning

confidence: 99%

O²-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Againstd-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays

Liu¹,

Saavedra²,

Lü³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

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 on D-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 g/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-B 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-␣-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-␣-mediated cell death pathways.

show abstract

“…Adenoviral iNOS gene transfer protected rat hepatocytes from spontaneous and TNF ϩ Actinomycin-D-induced apoptosis in vitro (61). In vivo, a NO donor decreased liver damage and blocked apoptosis in an animal model of acute liver failure (62,63), and NOS inhibitors increased apoptosis in LPSchallenged animals (63,64). NO blocked apoptosis by inhibiting caspase-3-like protease activity by several mechanisms (65,66).…”

Section: Figmentioning

confidence: 97%

GTP Cyclohydrolase I Is Coinduced in Hepatocytes Stimulated to Produce Nitric Oxide

Geller

Silvio

Billiar

et al. 2000

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Nitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice

Cited by 13 publications

References 32 publications

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

O²-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Againstd-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays

GTP Cyclohydrolase I Is Coinduced in Hepatocytes Stimulated to Produce Nitric Oxide

Contact Info

Product

Resources

About

Nitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice

Cited by 13 publications

References 32 publications

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

O2-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Againstd-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays

GTP Cyclohydrolase I Is Coinduced in Hepatocytes Stimulated to Produce Nitric Oxide

Contact Info

Product

Resources

About

O²-Vinyl 1-(Pyrrolidin-1-yl)diazen-1-ium-1,2-diolate Protection Againstd-Galactosamine/Endotoxin-Induced Hepatotoxicity in Mice: Genomic Analysis Using Microarrays