Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat

Gardner, Carol R.; Heck, Diane E.; Yang, Chung S.; Thomas, Paul E.; Zhang, Xu‐Jie; DeGeorge, George; Laskin, Jeffrey D.; Laskin, Debra L.

doi:10.1002/hep.510270316

Cited by 234 publications

(176 citation statements)

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“…NO is mainly produced by iNOS and contributes to tissue damages in various kinds of liver injury [36,37]. Consistently, we provided definitive evidence on the essential involvement of NO and iNOS also in APAPinduced liver injury [13].…”

Section: Discussionsupporting

confidence: 82%

“…Thus, the direct hepatotoxicities of APAP may induce liver injury in the early phase, but neutrophils subsequently infiltrate and aggravate the precedent liver injury probably by producing injurious factors. NO is mainly produced by iNOS and contributes to tissue damages in various kinds of liver injury [36,37]. Consistently, we provided definitive evidence on the essential involvement of NO and iNOS also in APAPinduced liver injury [13].…”

Section: The Roles Of Ho-1 In Apap-induced Liver Injurysupporting

confidence: 82%

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Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

et al. 2006

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Neutrophils and macrophages infiltrate after acetaminophen (APAP)-induced liver injury starts to develop. However, their precise roles still remain elusive. In untreated and control IgG-treated wild-type (WT) mice, intraperitoneal APAP administration (750 mg/kg) caused liver injury including centrilobular hepatic necrosis and infiltration of neutrophils and macrophages, with about 50% mortality within 48 h after the injection. APAP injection markedly augmented intrahepatic gene expression of inducible nitric oxide synthase (iNOS) and heme oxygenase (HO)-1. Moreover, neutrophils expressed iNOS, which is presumed to be an aggravating molecule for APAP-induced liver injury, while HO-1 was mainly expressed by macrophages. All antigranulocyte antibody-treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2)-deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and iNOS expression, indicating the pathogenic roles of neutrophils in APAPinduced liver injury. However, APAP caused more exaggerated liver injury in CXCR2-deficient mice with reduced macrophage infiltration and HO-1 gene expression, compared with neutropenic WT mice. An HO-1 inhibitor, tin-protoporphyrin-IX, significantly increased APAP-induced mortality, implicating HO-1 as a protective molecule for APAP-induced liver injury. Thus, CXCR2 may regulate the infiltration of both iNOS-expressing neutrophils and HO-1-expressing macrophages, and the balance between these two molecules may determine the outcome of APAP-induced liver injury. IntroductionAcetaminophen (APAP) is widely prescribed as an analgesic and antipyretic drug in clinics and is also sold as numerous over-counter preparations as a single compound or in combination with other medications [1, 2]. Although it is generally safe, an overdose of APAP can cause severe liver failure with a significant morbidity and mortality. Thus, its wide availability and severe toxicities has placed APAP overdose as the leading cause for calls to Poison Control Centers in the United States (>100 000/year). Moreover, APAP overdose accounts for more than 56 000 emergency room visits, 2600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year in the United States alone [3]. The toxic response is initiated by the metabolism of APAP to a toxic metabolite, N-acetyl-p-benzoquinone imine. Because N-acetyl-p-benzoquinone imine can react rapidly with sulfhydryl groups, it first depletes glutathione in hepatocytes and then reacts with a number of intracellular proteins, thereby causing their dysfuntions [4, 5]. APAP-induced liver injury is histopathologically characterized by centrilobular hepatic necrosis with a massive infiltration of leukocytes, particularly neutrophils. The recruitment of leukocytes in the damaged tissue is a hallmark of the inflammatory process, which may contribute to the development of APAP-induced liver injury [6,7]. In line with this assumption, accumulating evidence has implicated neutrophils as the leukocyte type essentially involved i...

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Section: Discussionsupporting

confidence: 82%

Section: The Roles Of Ho-1 In Apap-induced Liver Injurysupporting

confidence: 82%

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

et al. 2006

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“…To determine if SOD1 knockout exerted a general impact on hepatic protein nitration, we injected (intraperitoneal) mice with two different stimuli: APAP and lipopolysaccharide (LPS). The former is a widely used analgesic and antipyretic drug that raises plasma nitrate/nitrite concentrations and produces nitrotyrosine adducts in centrilobular areas of liver [24,25,27]. The latter induces the release of NO and superoxide in targeted tissues, leading to the formation of peroxynitrite and protein nitration [33,36].…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…The SOD1-/-and WT mice were generated from 129SVJ × C57BL/6 mice [1]. All used mice were 8-10 weeks old and were fed a diet containing adequate levels of all required [24,25,27]. The latter induces the release of NO and superoxide in targeted tissues, leading to the formation of peroxynitrite and protein nitration [33,36].…”

mentioning

confidence: 99%

Role of copper,zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver

Zhu

Zhang

Roneker

et al. 2008

Free Radical Biology and Medicine

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The solely known function of Cu,Zn-superoxide dismutase (SOD1) is to catalyze the dismutation of superoxide anion into hydrogen peroxide. Our objective was to determine if SOD1 catalyzed murine liver protein nitration induced by acetaminophen (APAP) and lipopolysaccharide (LPS). Liver and plasma samples were collected from young adult SOD1 knockout mice (SOD1-/-) and wild-type (WT) mice at 5 or 6 h after an ip injection of saline, APAP, or LPS. Hepatic nitrotyrosine formation was induced by APAP and LPS only in the WT mice. The diminished hepatic protein nitration in the SOD1-/-mice was not directly related to plasma nitrite and nitrate concentrations. Similar genotype differences were seen in liver homogenates treated with a bolus of peroxynitrite. Adding only the holo, but not the apo-SOD1 enzyme into the liver homogenates enhanced the reaction in an activity-dependent fashion and nearly eliminated the genotype difference at the high doses. Mass Spectrometry showed 4 more nitrotyrosine residues in bovine serum albumin and 10 more nitrated protein candidates in the SOD1-/-liver homogenates by peroxynitrite with added SOD1. In conclusion, the diminished hepatic protein nitration mediated by APAP or LPS in the SOD1-/-mice was due to the lack of SOD1 activity per se. Keywords SOD1; Protein nitration; Acetaminophen; Peroxynitrite; Lipopolysaccharide; Mouse Although copper,zinc-superoxide dismutase (SOD1) has been widely considered a major intracellular antioxidant enzyme in mammals, its solely known function is to catalyze the conversion of superoxide anion into less active hydrogen peroxide. Indeed, SOD1 is protective against oxidative stress associated with acute paraquat toxicity, myocardial ischemia/reperfusion injury, and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration [1][2][3]. Mice deficient in SOD1 develop Address correspondence to: Xin Gen Lei, Department of Animal Science, Cornell University, Ithaca, NY 14853, Tel. 607-254-4703; Fax. 607-255-9829; E-Mail: XL20@cornell.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [7,8]. These paradoxical findings strongly suggest that SOD1 may exert functions more than just superoxide dismutation. In fact, SOD1 was shown to promote peroxynitrite-mediated nitrotyrosine formation in vitro [9,10]. NIH Public AccessPeroxynitrite is formed by a rapid diffusion-limited, radical-radical coupling reaction between nitric oxide (NO) and superoxide anion [11,12] [24,25,33,34] provide us with an unprecedented opportunity to study the in vivo role of SOD1 in nitrotyrosine formation. Furtherm...

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“…For example, the induction of iNOS that accompanies the inflammatory response to acetaminophen-induced injury is associated with an NO-dependent exacerbation of pericentral necrosis. 60 This is likely mediated by peroxynitrite because histological sections from livers of acetominophen-treated rats are found to be positive for nitrotyrosine, considered to be a ''footprint'' of peroxynitrite. 61 Similar synergy has been reported in paraquat toxicity, with potentiation of the mitochondrial permeability transition.…”

Section: Cellular and Metabolic Effectsmentioning

confidence: 99%