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

Liu, J

doi:10.1053/jhep.2003.50063

Cited by 80 publications

(53 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Liver toxicity from APAP overdosing ensues when the drug is metabolized by P-450 enzymes to produce the highly toxic metabolite, N-acetylp-benzo-quinone imine. Under normal circumstances N-acetyl-p-benzo-quinone imine is inactivated through conjugation with GSH, 7 but on APAP overdose, GSH is depleted and the formation of N-para-aminoquinonimine is strongly increased. As a result, this reactive metabolite binds covalently to cellular macromolecules 8 leading to a potentially fatal centrilobular hepatic necrosis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Zanobbio

Palazzo

Gariboldi

et al. 2009

The American Journal of Pathology

View full text Add to dashboard Cite

Superiore di Sanità, Rome; and the Istituto Nazionale per lo Studio e la Cura dei Tumori, ‡ Milan, ItalyWe have recently observed that oral administration of D-glucose saves animals from lipopolysaccharide (LPS)-induced death. This effect is the likely consequence of glucose-induced activation of the sodiumdependent glucose transporter-1. In this study, we investigated possible hepatoprotective effects of glucose-induced, sodium-dependent, glucose transporter-1 activation. We show that oral administration of D-glucose , but not of either D-fructose or sucrose, prevents LPS-induced liver injury, as well as liver injury and death induced by an overdose of acetaminophen. In both of these models, physiological liver morphology is maintained and organ protection is confirmed by unchanged levels of the circulating markers of hepatotoxicity, such as alanine transaminase or lactate dehydrogenase. In addition, D-glucose was found to protect the liver from ␣-amanitin-induced liver injury. In this case, in contrast to the previously described models, a second signal had to be present in addition to glucose to achieve protective efficacy. Toll-like receptor 4 stimulation that was induced by low doses of LPS was identified as such a second signal. Eventually, the protective effect of orally administered glucose on liver injury induced by LPS, overdose of acetaminophen, or ␣-amanitin was shown to be mediated by the anti-inflammatory cytokine interleukin-10. Liver failure is one of the most devastating syndromes observed in clinical practice. It is associated with high overall mortality, ranging from 30% to 80%, depending on the underlying etiology. 1,2 The most common etiologies are acute viral hepatitis, drug overdose, idiosyncratic drug reactions, and ingestion of other toxins.3 Insulting agents can cause hepatocyte death through different mechanisms of action, and when the amount of functioning cells decreases to a level at which the organ is no longer capable of fulfilling its metabolic and synthetic tasks, hepatic failure takes place. 4 Recently we demonstrated, in a murine model of septic shock, that oral administration of D-glucose saves mice from death, most likely as a result of glucose-induced activation of the intestinal sodium-dependent glucose transporter-1 (SGLT-1).5 Using this model, we made preliminary observations that the liver, one of the organs most severely affected by lipopolysaccharide and D-galactosamine (LPS/D-GalN) treatment, was protected by oral administration of D-glucose. The expression of SGLT-1 on the apical membrane of enterocytes and the observation that protection from LPS shock was observed only on oral administration of D-glucose, but not on i.p. administration, suggested an important role of intestinal epithelial cells in protection from LPS-induced injury to the liver and other organs.Here, we report on a more extensive investigation on the hepatoprotective effect of orally administered D-glucose. Glucose was evaluated in LPS-induced shock, as well as in two other models of acute liver f...

show abstract

Section: Discussionmentioning

confidence: 99%

“…APAP overdose is a common cause of druginduced liver injury 6 since this drug, when administered at very elevated doses, generates the highly reactive intermediate, N-para-aminoquinonimine, 7 which covalently binds to hepatocyte macromolecules, leading to cellular death. 8 This can lead to a potentially fatal centrilobular hepatic necrosis.…”

mentioning

confidence: 99%

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Zanobbio

Palazzo

Gariboldi

et al. 2009

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…33,34 Furthermore, NAPQI is a highly reactive intermediate that by itself can contribute to oxidative damage. 35 The increase in oxidative stress and the presence of necrotic hepatocytes can lead to activation of Kupffer cells, which in turn further exacerbates liver injury. 36 Our data support a role for LBP in the pathogenesis of acetaminophen-induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice

Gong

Fan

et al. 2005

Hepatology

View full text Add to dashboard Cite

Acetaminophen toxicity is the most common cause of acute liver failure in the United States and Europe. Although much is known about the metabolism of acetaminophen, many questions remain regarding the pathogenesis of liver injury. In this study, we examined the role of lipopolysaccharide-binding protein (LBP), a protein important in mediating cellular response to lipopolysaccharides, by using LBP wild-type and knockout (KO) mice. We found that LBP KO mice were protected from acetaminophen-induced hepatotoxicity. At 350 mg/kg of acetaminophen, LBP KO mice had significantly less liver injury and necrosis than wild-type mice. Repletion studies in LBP KO mice using an LBP-adenoviral construct resulted in significantly more hepatic injury and necrosis after acetaminophen exposure compared with mice receiving the control adenoviral construct. In conclusion, LBP KO mice are protected from toxicity with a decrease in hepatic necrosis following acetaminophen challenge. This suggests a novel role for LBP in modulating acetaminophen-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website

show abstract

“…O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a stable diazeniumdiolate, which can circulate freely in the body until it is metabolized to release NO by cytochrome P450 in the liver, providing a significant level of local hepatic NO [9]. V-PYRRO/NO mitigates the hepatotoxicity of various compounds in vivo and in vitro [10][11][12]. For instance, V-PYRRO/NO can protect against LPS-induced liver injury in mice, an effect that is linked to suppression of apoptosis and NF-κB expression [11].…”

Section: Introductionmentioning

confidence: 99%

“…V-PYRRO/NO also reduces TNF-α-induced liver injury associated with reduced hepatocellular apoptosis [9]. V-PYRRO/NO pretreatment can similarly reduce both the hepatotoxic effects of acetaminophen and cadmium in mice [12,13]. Furthermore, V-PYRRO/ NO reduces cadmium toxicity and apoptosis directly on the cellular level in liver cells [14], indicating that it's protective effects are not just based in organ-level alterations in vivo toxicokinetics, potentially due to enhanced vascular capacity from NO-induced vasodilation.…”

Section: Introductionmentioning

confidence: 99%

The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

Liu

Fuquay

et al. 2007

Cancer Letters

View full text Add to dashboard Cite

Arsenite is an important cancer chemotherapeutic. The liver is a major target tissue of arsenic toxicity and hepatotoxicity may limit its chemotherapeutic efficacy. O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a liver-selective nitric oxide (NO)-producing prodrug metabolized by hepatic P450 enzymes to release NO locally. V-PYRRO/NO protects against various organic or inorganic hepatotoxicants but any role in arsenic hepatotoxicity is undefined. Thus, we studied the effects of V-PYRRO/NO (0-1000 μM) pretreatment on inorganic arsenic-induced toxicity in cultured rat liver (TRL 1215) cells. These cells metabolized the prodrug to release NO, producing extracellular nitrite levels to 41.7-fold above control levels (7.50 ± 0.38 μM) after 24 h V-PYRRO/ NO (1000 μM) exposure. The effect of pretreatment with V-PYRRO/NO (24 h) on the cytolethality of arsenic (as NaAsO 2 ) exposure (24 h) was assessed. Arsenic was markedly less toxic in V-PYRRO/ NO pretreated cells (LC 50 = 30.3 μM) compared to control (LC 50 = 20.1 μM) and the increases in LC 50 showed a direct relationship to the level of NO produced (measured as nitrite). Consistent with the cytolethality data, V-PYRRO/NO pretreatment markedly reduced arsenic-induced apoptosis as assessed by DNA fragmentation. Activation of the c-Jun N-terminal kinase (JNK) pathway can be critical to apoptosis and pretreatment with V-PYRRO/NO suppressed arsenic-induced JNK activation. V-PYRRO/NO pretreatment modestly increased metallothionein (MT), a metal-binding protein, but greatly enhanced arsenic induction of MT. Thus, V-PYRRO/NO pretreatment directly mitigates arsenic toxicity in cultured liver cells, reducing cytolethality, apoptosis and related JNK pathway activation, apparently through generation of NO. The role of NO in reducing the hepatotoxicity of arsenical chemotherapeutics in vivo deserves additional study.

show abstract

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

Cited by 80 publications

References 31 publications

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice

The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

Contact Info

Product

Resources

About