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Acad Emerg Med. 2006 May;13(5):479-85. Epub 2006 Mar 21.

Endothelially derived nitric oxide affects the severity of early acetaminophen-induced hepatic injury in mice.

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  • 1Department of Emergency Medicine, Beth Israel Deaconess Hospital, Boston, MA, USA.

Abstract

OBJECTIVES:

The precise mechanism of hepatocellular toxicity following acetaminophen (APAP) poisoning remains unclear. Nitric oxide is implicated in APAP toxicity as an inflammatory signaling molecule and as a precursor to the free radical peroxynitrate. The effects of inducible nitric oxide synthase (iNOS)-derived NO in APAP toxicity are known; however, the role of endothelial nitric oxide synthase (eNOS)-derived NO is unknown. The authors sought to evaluate the effect of eNOS-derived NO during APAP toxicity.

METHODS:

C57BL6/J mice deficient in eNOS (eNOS KO) or iNOS (iNOS KO) and wild-type mice (WT) were treated with 300 mg/kg APAP. Alanine aminotransferase levels and plasma nitrate and nitrite levels were measured. Hypoxia inducible factor (HIF)-1alpha and Glucose Transporter 1 (Glut-1) levels were determined by Western blot.

RESULTS:

Alanine aminotransferase levels were significantly elevated in all treated animals. Alanine aminotransferase levels were significantly lower in eNOS KO and iNOS KO than in treated WT animals. Plasma nitrate/nitrite levels were significantly higher in WT animals than in iNOS KO and eNOS KO animals. HIF-1alpha expression was increased in WT mice and decreased in iNOS KO mice. Glut-1 is a downstream, indirect marker of HIF function. Glut-1 expression was increased in WT and eNOS KO mice.

CONCLUSIONS:

Deficiency of either iNOS or eNOS results in decreased NO production and is associated with reduced hepatocellular injury following APAP poisoning. HIF-1alpha and Glut-1 levels are increased following APAP poisoning, implying that HIF-1alpha is functional during the pathogenic response to APAP poisoning.

Comment in

PMID:
16551773
[PubMed - indexed for MEDLINE]
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