Peroxynitrite and drug-dependent toxicity

doi:10.1016/j.tox.2004.11.023

Toxicology

Volume 208, Issue 2, 15 March 2005, Pages 273-288

https://doi.org/10.1016/j.tox.2004.11.023 Get rights and content

Abstract

Peroxynitrite is the product of the diffusion-controlled termination reaction between two radicals, nitric oxide and superoxide and is a strong oxidant and nitrating intermediate. Critical biomolecules like proteins, lipids and DNA react with peroxynitrite via direct or radical-mediated mechanisms, resulting in alterations in enzyme activities and signaling pathways. The biological consequences of peroxynitrite-mediated oxidative modifications depend on the levels of oxidant achieved in vivo and its cellular site of production. High and prolonged fluxes of peroxynitrite that overcome the endogenous antioxidant mechanisms, end up in disruption of cell homeostasis leading to apoptotic or necrotic cell death. Several drugs used in modern medicine and agriculture can exert their toxic side effects through mechanisms involving the formation of toxic levels of peroxynitrite, via redox cycling, uncoupling of nitric oxide synthase, stimulation of the endogenous formation of nitric oxide and superoxide or lowering of the antioxidant defenses. Experimental evidence point to peroxynitrite participation in the toxicity of doxorubicin, paraquat, acetaminophen and MPTP (N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine). The pharmacology against peroxynitrite-mediated toxicity could be oriented towards decreasing the levels of the precursor radicals (i.e. using NOS or oxidases inhibitors, SOD mimetics) or reducing the levels of peroxynitrite itself (peroxynitrite scavengers or decomposition catalysts) and serve to attenuate or neutralize drug-dependent toxicity linked to enhanced peroxynitrite formation.

Introduction

Excess production of the free radicals, nitric oxide (NO) and superoxide (O₂⁻), is related to cell and tissue pathology (Freeman and Crapo, 1982, White et al., 1994, Beckman and Koppenol, 1996, Radi et al., 2000, Turko and Murad, 2002). Nitric oxide is enzymatically produced from l-arginine by nitric oxide synthase (NOS). Three isoforms of this enzyme have been described: nNOS (neuronal), eNOS (endothelial) and iNOS (induced, inflammatory). On the other hand, superoxide can be catalytically produced (for example, by xanthine oxidase or NADPH oxidase), and also formed by partial reduction of oxygen in the mitochondrial membrane or non-enzymatic monoelectron reduction of oxygen (for example, hemoglobin autoxidation). The termination reaction between NO and O₂⁻ is diffusion-controlled (k = 10¹⁰ M⁻¹ s⁻¹) and the product of this reaction is peroxynitrite anion (ONOO⁻). Considering the diffusional properties of the precursor radicals (Lynch and Fridovich, 1978, Denicola et al., 1996b), peroxynitrite¹ is predominantly formed close to the site of O₂⁻ generation (Chen et al., 1998, Chen and Deen, 2001). Peroxynitrite has a short biological half-life (10–20 ms) but can cross biological membranes and diffuse one to two cell diameters (Denicola et al., 1998). In vivo formation of peroxynitrite is supported by everyday growing experimental evidence (Estevez et al., 1999, Radi et al., 2002, Turko and Murad, 2002, Fries et al., 2003).

Section snippets

Why is peroxynitrite toxic?

Peroxynitrite is not a radical but is a stronger oxidant than its precursor radicals. It is a weak acid, with a pK_a of 6.8, therefore, under physiological conditions, both the protonated (ONOOH) and anionic (ONOO⁻) forms are present.

Peroxynitrite can directly react with target biomolecules via one- or two-electron oxidations. These direct reactions are first-order in peroxynitrite and in the target, thus the oxidation is faster at higher concentrations of the target present. The second-order

Toxicology of peroxynitrite

There are several drugs and foreign agents used in modern medicine and agriculture that exert their toxic side effects through mechanisms involving the formation of toxic levels of peroxynitrite. The possible mechanisms are:

(a)
The drug undergoes redox cycling, i.e. it is reduced by a cellular system to yield an intermediate that is then oxidized by O₂ to produce O₂⁻, and at the same time and place, a flux of NO is produced.
(b)
The drug stimulates endogenous production of NO and O₂⁻ (for example,

Pharmacology against peroxynitrite-mediated toxicity

Since peroxynitrite is formed in vivo by reaction of radical dot NO and O₂⁻, any drug that prevents the formation of any of these radicals, will end up in a reduction of peroxynitrite. In this context, inhibitors of NOS, inhibitors of oxidases and/or SOD mimetics could be pharmacologically used (Scheme 3). Another approach could be to reduce the levels of peroxynitrite been form by using peroxynitrite scavengers or decomposition catalysts (Scheme 3). The search for effective pharmacological interventions

Concluding remarks

Peroxynitrite formed in vivo from superoxide and nitric oxide can mediate selective oxidation and nitration of biomolecules via direct or radical-dependent pathways. Depending on the levels and cellular sites of peroxynitrite produced, these oxidative modifications can lead to conformational changes, impaired functions, enzyme inactivation, or signaling pathways alterations, that can overcome the endogenous antioxidant mechanisms and result in disruption of cell homeostasis and potentially

Acknowledgments

This work was supported by grants from Howard Hughes Medical Institute and NIH-FIRCA. RR is an International Research Scholar of the Howard Hughes Medical Institute.

References (180)

B. Alvarez et al.
Kinetics of peroxynitrite reaction with amino acids and human serum albumin
J. Biol. Chem.
(1999)
O. Augusto et al.
Nitrogen dioxide and carbonate radical anion: two emerging radicals in biology
Free Radic. Biol. Med.
(2002)
S. Bartesaghi et al.
Reactions of desferrioxamine with peroxynitrite-derived carbonate and nitrogen dioxide radicals
Free Radic. Biol. Med.
(2004)
M.V. Beligni et al.
Nitric oxide protects against cellular damage produced by methylviologen herbicides in potato plants
Nitric Oxide
(1999)
B. Blanchard-Fillion et al.
Nitration and inactivation of tyrosine hydroxylase by peroxynitrite
J. Biol. Chem.
(2001)
S. Burney et al.
The chemistry of DNA damage from nitric oxide and peroxynitrite
Mutat. Res.
(1999)
A.M. Cassina et al.
Cytochrome c nitration by peroxynitrite
J. Biol. Chem.
(2000)
L. Castro et al.
Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide
J. Biol. Chem.
(1994)
C. Cecchi et al.
Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients
Free Radic. Biol. Med.
(2002)
B. Chen et al.
Diffusion and reaction of nitric oxide in suspension cell cultures
Biophys. J.
(1998)

L. Clejan et al.

Synergistic interactions between NADPH-cytochrome P-450 reductase, paraquat, and iron in the generation of active oxygen radicals

Biochem. Pharmacol.

(1989)

P. Costantini et al.

On the effects of paraquat on isolated mitochondriaEvidence that paraquat causes opening of the cyclosporin A-sensitive permeability transition pore synergistically with nitric oxide

Toxicology

(1995)

S. Cuzzocrea et al.

Antiinflammatory effects of mercaptoethylguanidine, a combined inhibitor of nitric oxide synthase and peroxynitrite scavenger, in carrageenan-induced models of inflammation

Free Radic. Biol. Med.

(1998)

B.J. Day et al.

A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced lung injury in vivo

Toxicol. Appl. Pharmacol.

(1996)

J.A. DeGray et al.

Reduction of paraquat and related bipyridylium compounds to free radical metabolites by rat hepatocytes

Arch. Biochem. Biophys.

(1991)

A. Denicola et al.

Peroxynitrite reaction with carbon dioxide/bicarbonate: kinetics and influence on peroxynitrite-mediated oxidations

Arch. Biochem. Biophys.

(1996)

A. Denicola et al.

Desferrioxamine inhibition of the hydroxyl radical-like reactivity of peroxynitrite: role of the hydroxamic groups

Free Radic. Biol. Med.

(1995)

A. Denicola et al.

Nitric oxide diffusion in membranes determined by fluorescence quenching

Arch. Biochem. Biophys.

(1996)

J.H. Doroshow et al.

Redox cycling of anthracyclines by cardiac mitochondriaII. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical

J. Biol. Chem.

(1986)

G. Ferrer-Sueta et al.

Reactions of manganese porphyrins with peroxynitrite and carbonate radical anion

J. Biol. Chem.

(2003)

D.M. Fries et al.

Expression of inducible nitric-oxide synthase and intracellular protein tyrosine nitration in vascular smooth muscle cells: role of reactive oxygen species

J. Biol. Chem.

(2003)

J. Haendeler et al.

Effects of redox-related congeners of NO on apoptosis and caspase-3 activity

Nitric Oxide

(1997)

R.E. Heikkila et al.

Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity

Neurosci. Lett.

(1985)

S. Herold

Nitrotyrosine, dityrosine, and nitrotryptophan formation from metmyoglobin, hydrogen peroxide, and nitrite

Free Radic. Biol. Med.

(2004)

H. Ischiropoulos

Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species

Arch. Biochem. Biophys.

(1998)

H. Ischiropoulos et al.

Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase

Arch. Biochem. Biophys.

(1992)

B. Kalyanaraman et al.

Spin-trapping and direct electron spin resonance investigations of the redox metabolism of quinone anticancer drugs

Biochim. Biophys. Acta

(1980)

L.K. Klaidman et al.

Redox cycling of MPP⁺: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase

Free Radic. Biol. Med.

(1993)

B.M. Klebl et al.

Protein oxidation, tyrosine nitration, and inactivation of sarcoplasmic reticulum Ca²⁺-ATPase in low-frequency stimulated rabbit muscle

FEBS Lett.

(1998)

E.A. Konorev et al.

Rapid and irreversible inhibition of creatine kinase by peroxynitrite

FEBS Lett.

(1998)

J. Krall et al.

Superoxide mediates the toxicity of paraquat for cultured mammalian cells

J. Biol. Chem.

(1988)

D.M. Kuhn et al.

Peroxynitrite inactivates tryptophan hydroxylase via sulfhydryl oxidationCoincident nitration of enzyme tyrosyl residues has minimal impact on catalytic activity

J. Biol. Chem.

(1999)

C.I. Lee et al.

Regulation of xanthine oxidase by nitric oxide and peroxynitrite

J. Biol. Chem.

(2000)

R.E. Lynch et al.

Permeation of the erythrocyte stroma by superoxide radical

J. Biol. Chem.

(1978)

L.A. MacMillan-Crow et al.

Tyrosine nitration of c-SRC tyrosine kinase in human pancreatic ductal adenocarcinoma

Arch. Biochem. Biophys.

(2000)

A.S. Margolis et al.

Role of paraquat in the uncoupling of nitric oxide synthase

Biochim. Biophys. Acta

(2000)

B. Alvarez et al.

Peroxynitrite reactivity with amino acids and proteins

Amino Acids

(2003)

B. Alvarez et al.

Peroxynitrite-dependent tryptophan nitration

Chem. Res. Toxicol.

(1996)

B.N. Ames et al.

Oxidants, antioxidants, and the degenerative diseases of aging

Proc. Natl. Acad. Sci. U.S.A.

(1993)

J. Ara et al.

Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Proc. Natl. Acad. Sci. U.S.A.

(1998)

J.S. Beckman et al.

Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide

Proc. Natl. Acad. Sci. U.S.A.

(1990)

J.S. Beckman et al.

Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly

Am. J. Physiol.

(1996)

J.S. Beckman et al.

Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry

Biol. Chem. Hoppe Seyler

(1994)

B. Beltran et al.

The effect of nitric oxide on cell respiration: a key to understanding its role in cell survival or death

Proc. Natl. Acad. Sci. U.S.A.

(2000)

H.I. Berisha et al.

Nitric oxide as a mediator of oxidant lung injury due to paraquat

Proc. Natl. Acad. Sci. U.S.A.

(1994)

B.S. Berlett et al.

Carbon dioxide stimulates peroxynitrite-mediated nitration of tyrosine residues and inhibits oxidation of methionine residues of glutamine synthetase: both modifications mimic effects of adenylylation

Proc. Natl. Acad. Sci. U.S.A.

(1998)

K. Bian et al.

The nature of heme/iron-induced protein tyrosine nitration

Proc. Natl. Acad. Sci. U.S.A.

(2003)

R.H. Blum et al.

AdriamycinA new anticancer drug with significant clinical activity

Ann. Intern. Med.

(1974)

C. Brito et al.

Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death

J. Immunol.

(1999)

R. Bryk et al.

Peroxynitrite reductase activity of bacterial peroxiredoxins

Nature

(2000)

Cited by (122)

A highly sensitive and selective chemiluminescent probe for peroxynitrite detection in vitro, in vivo and in human liver cancer tissue
2024, Journal of Hazardous Materials
Peroxynitrite (ONOO⁻) is one of the important active nitrogen/reactive oxygen species that plays various roles in biological processes, such as inducing apoptosis and necrosis. Recent studies have shown that a significant increases in ONOO⁻ content during tumor development, which is closely related to the level of oxidative stress within the tumor. It has been found that herbicide paraquat (PQ) can significantly increase the level of ONOO⁻ in cells. Therefore, accurate monitoring abnormal changes in ONOO⁻ caused by environmental hazardous materials and tumors is helpful in promoting the diagnosis and treatment of oxidative stress diseases (tumors), evenly environmental detection. Currently, traditional fluorescent probes for ONOO⁻ detection have background interference. To address this, we developed a chemiluminescent probe (CL-1) and a fluorescent probe (Flu-1), using diphenyl phosphonate as a recognition group. CL-1 shows extremely sensitivity (9.8 nM), a high signal-to-noise(S/N) ratio (502), and excellent bioimaging capabilities compared to fluorescent probe (Flu-1). We have successfully used CL-1 to detect ONOO⁻ produced by PQ stimulated cells, as well as endogenous ONOO⁻ in tumor cells, mice, and human liver cancer tissues. Therefore, CL-1 can not only be a valuable tool for visualizing tumor and studying the role of ONOO⁻ in tumor pathology, but the probe has the potential to be a powerful molecular imaging tool for exploring the complex biological role of ONOO⁻ in a variety of biological Settings.
Nilotinib alleviates paraquat-induced hepatic and pulmonary injury in rats via the Nrf2/Nf-kB axis
2023, International Immunopharmacology
Paraquat (PQ, 1,1′-dimethyl-4-4′-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. It exerts its toxic effects mainly as a result of its redox cycle via the production of superoxide anions in organisms, leading to an imbalance in the redox state of the cell causing oxidative damage and finally cell death. The aim of this study was to estimate the beneficial protective role of nilotinib (NIL) on PQ-induced hepatic and pulmonary toxicity in rats.
Male wistar rats were randomly divided into four groups, namely control, PQ (15 mg/kg), PQ plus NIL (5 mg/kg) and PQ plus NIL (10 mg/kg). NIL (5 and 10 mg/kg/day) was taken by oral syringe for five days followed by a single intra-peritoneal administration of PQ (15 mg/kg) on sixth day.
Pretreatment with NIL relieved the histological damage in liver and lung tissues and improved hepatic biochemical markers. It significantly (p < 0.05) reduced serum levels of ALT, AST, ALP, Y-GT and total bilirubin while increased that of albumin. Meanwhile, NIL significantly (p < 0.05) reduced oxidative stress markers via reduction of malondialdhyde (MDA) and elevation of glutathione (GSH) contents in liver and lung tissues. In addition, it significantly (p < 0.05) decreased the inflammation by reducing hepatic and pulmonary tumor necrosis factor alpha (TNF-α) and nuclear transcription factor kappa B (NF-KB/p65) contents. Nilotinib also down-regulated apoptosis by reducing cysteinyl aspartate-specific proteinase-3 (caspase-3). Furthermore, it upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) in liver and lung tissues.
NIL suppressed PQ-induced inflammation, oxidative stress and apoptosis in liver and lung tissues by modulating Nrf2/Nf-kB axis.
A mitochondria-targeted supramolecular nanoplatform for peroxynitrite-potentiated oxidative therapy of orthotopic hepatoma
2022, Biomaterials
Oxidative therapy, which generates reactive oxygen species (ROS) via intracellular enzymatic reactions to achieve tumor ablation, is considered as an emerging approach to cancer treatment. Herein, nitric oxide (NO)-combined oxidative therapy is reported by integrating glutathione (GSH)-sensitive NO donor and pH-sensitive cinnamaldehyde (CA) prodrug into a mitochondria-targeted drug nanocarrier, which is prepared by the host-guest interaction between α-cyclodextrin (α-CD) and polyethylene glycol (PEG). After internalized by cancer cells, CA can be released in acidic endo/lysosome and finally induce ROS generation in mitochondria for oxidative therapy. At the same time, NO can be targeted delivered to mitochondria by a mitochondria-targeting strategy and then realize selective release of NO in mitochondria. NO can deplete intracellular predominant antioxidant GSH, which will enhance oxidative therapy of CA. Furthermore, peroxynitrite (ONOO⁻) with strong peroxidation and nitration capability can be produced in mitochondria by the reaction between NO and ROS for reactive nitrogen species (RNS)-mediated oxidative therapy. The generation of ONOO⁻ in mitochondria is very effective in facilitating mitochondrial membrane permeabilization, which can cause mitochondrial dysfunction and finally induce mitochondrial apoptosis. The antitumor ability of mitochondria-targeted ONOO⁻-potentiated oxidative therapy is fully investigated on subcutaneous and orthotopic hepatoma model on nude mice. This innovative strategy for the selective generation of ONOO⁻ in mitochondria may serve as an afflatus for future applications in cancer treatment.
Chymase inhibition: A key factor in the anti-inflammatory activity of ethanolic extracts and spilanthol isolated from Acmella oleracea
2021, Journal of Ethnopharmacology
Acmella oleracea (L.) R. K. Jansen (Asteraceae), known as jambú in Brazil, is used in traditional medicine as analgesic and for inflammatory conditions, characterized by the presence of N-alkylamides, mainly spilanthol. This bioactive compound is responsible for the above-described pharmacological properties, including sialagogue and anesthetic.
This study aimed to characterize the anti-inflammatory effects of A. oleracea leaves (AOEE-L) and flowers (AOEE-F) extracts, including an isolated alkylamide (spilanthol), using in vitro and in vivo models. The mechanism underlying this effect was also investigated.
Extracts were analyzed by HPLC-ESI-MS/MS in order to characterize the N-alkylamides content. AOEE-L, AOEE-F (25–100 μg/mL) and spilanthol (50–200 μM) were tested in vitro on VSMC after stimulation with hyperglycemic medium (25 mM glucose). Their effects over nitric oxide (NO) generation, chymase inhibition and expression, catalase (CAT), superoxide anion (SOD) radical activity were evaluated. After an acute administration of extracts (10–100 mg/mL) and spilanthol (6.2 mg/mL), the anti-inflammatory effects were evaluated by applying the formalin test in rats. Blood was collected to measure serum aminotransferases activities, NO activity, creatinine and urea.
A number of distinct N-alkylamides were detected and quantified in AOEE-L and AOEE-F. Spilanthol was identified in both extracts and selected for experimental tests. Hyperglycemic stimulation in VSMC promoted the expression of inflammatory parameters, including chymase, NO, CAT and SOD activity and chymase expression, all of them attenuated by the presence of the extracts and spilanthol. The administration of extracts or spilanthol significantly inhibited edema formation, NO production and cell tissue infiltration in the formalin test, without causing kidney and liver toxicity.
Taken together, these results provide evidence for the anti-inflammatory activity of leaves and flowers extracts of jambú associated distinctly with their chemical profile. The effects appear to be associated with the inhibition of chymase activity, suppression of the proinflammatory cytokine NO and antioxidant activities.
A fast detection of peroxynitrite in living cells
2020, Analytica Chimica Acta
Citation Excerpt :
It plays a dominant role in cellular signal transduction pathway [3] and antimicrobial activities [4]. However, excessive ONOO− can oxidize multiple target molecules or generate secondary free radicals with highly reactivity [5], resulting in structural modifications and dysfunctions of proteins [6], nucleic acids [7] and lipids [8] with significant cytotoxic consequences. Consequently, the development of sensitive and selective methods for ONOO− is urgently required.
Peroxynitrite (ONOO⁻) plays a crucial role in the regulation of diverse pathophysiological processes, and high level of ONOO⁻ is profound association with numerous diseases. Herein, we developed an anthraquinone-based fluorescent probe L for ONOO⁻ determination by a new recognition mechanism: amido oxidized nitroso-group by ONOO⁻. Probe L with amine-based recognition receptor is more selective to ONOO⁻ than other reactive oxygen species, including H₂O₂ and ClO⁻. Furthermore, ONOO⁻ could be rapidly detected by probe L with a Limit of Detection of 13 nM. More importantly, L could be used to monitor intracellular ONOO⁻ in SMMC-7721 cells.
Acute acetaminophen intoxication induces direct neurotoxicity in rats manifested as astrogliosis and decreased dopaminergic markers in brain areas associated with locomotor regulation
2019, Biochemical Pharmacology
Citation Excerpt :
Excess generation of NAPQI leads to depletion of hepatocellular GSH pool [16], with the unneutralized NAPQI binding to nucleophilic macromolecules (proteins, DNA and unsaturated lipids) resulting in hepatocellular damage through multi-factorial mechanism(s) [17]. Among the key mechanistic events associated with APAP toxicity, increase in oxidative stress via generation of reactive oxygen species (ROS) [18], glutathione disulfide (GSSG) formation [19,20] and nitric oxide (NO) derivatives generation [21] are seen in association with toxic APAP exposure (for a complete review of APAP toxicity see Du et al. [22]). While APAP administration is safe at therapeutic doses, its excessive use can lead to hepatotoxicity ranging from mild injury to ALF [23].
Acetaminophen (APAP) administration at therapeutic doses is safe, however overdosing produces hepatocellular injury via a multifactorial mechanism(s) that involves generation of reactive oxygen species (ROS), being the most common cause of acute liver failure (ALF) in the northern hemisphere. Brain alterations induced by APAP intoxication are usually considered secondary to hepatic encephalopathy development due to ALF. Although APAP is primarily metabolized in the liver, it is also distributed and metabolized homogeneously in the brain, affecting brain redox status. Nevertheless, comprehensive studies on the potential of APAP intoxication to produce brain toxicity are scarce. The aim of this study was to characterize the direct toxic effects of APAP in different regions of the brain and on behavior in rats where the magnitude of hepatotoxicity produced is not associated with ALF.
The present work demonstrates that APAP intoxication producing hepatotoxicity, but not ALF in rats, is associated with marked hypolocomotion. Our studies also suggest that selective downregulation in dopamine levels in brain areas that regulate motor activity may be responsible, in part, for the decreased locomotion observed with APAP treatment. Furthermore, we observed that the brain histoarchitecture is conserved and that edema is not present. However, an increase in oxidative stress, reactive astrogliosis and a decrease in neuron processes are the main features observed in APAP-intoxicated animals. These effects might be partly due to direct toxic effects of APAP in brain, since the same reactive astrogliosis observed in rats was also observed in rat primary astrocyte cultures exposed to APAP.

View all citing articles on Scopus

View full text

Peroxynitrite and drug-dependent toxicity

Abstract

Introduction

Section snippets

Why is peroxynitrite toxic?

Toxicology of peroxynitrite

Pharmacology against peroxynitrite-mediated toxicity

Concluding remarks

Acknowledgments

J. Biol. Chem.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Nitric Oxide

J. Biol. Chem.

Mutat. Res.

J. Biol. Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

Biophys. J.

Biochem. Pharmacol.

Toxicology

Free Radic. Biol. Med.

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Nitric Oxide

Neurosci. Lett.

Free Radic. Biol. Med.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Biochim. Biophys. Acta

Free Radic. Biol. Med.

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Biochim. Biophys. Acta

Peroxynitrite reactivity with amino acids and proteins

Amino Acids

Peroxynitrite-dependent tryptophan nitration

Chem. Res. Toxicol.

Oxidants, antioxidants, and the degenerative diseases of aging

Proc. Natl. Acad. Sci. U.S.A.

Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Proc. Natl. Acad. Sci. U.S.A.

Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide

Proc. Natl. Acad. Sci. U.S.A.

Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly

Am. J. Physiol.

Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry

Biol. Chem. Hoppe Seyler

The effect of nitric oxide on cell respiration: a key to understanding its role in cell survival or death

Proc. Natl. Acad. Sci. U.S.A.

Nitric oxide as a mediator of oxidant lung injury due to paraquat

Proc. Natl. Acad. Sci. U.S.A.

Carbon dioxide stimulates peroxynitrite-mediated nitration of tyrosine residues and inhibits oxidation of methionine residues of glutamine synthetase: both modifications mimic effects of adenylylation

Proc. Natl. Acad. Sci. U.S.A.

The nature of heme/iron-induced protein tyrosine nitration

Proc. Natl. Acad. Sci. U.S.A.

AdriamycinA new anticancer drug with significant clinical activity

Ann. Intern. Med.

Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death

J. Immunol.

Peroxynitrite reductase activity of bacterial peroxiredoxins

Nature