Role of cytochrome P-450 in the stimulation of microsomal production of reactive oxygen species by ferritin

Puntarulo, Susana; Cederbaum, Arthur I.

doi:10.1016/0304-4165(95)00157-3

Cited by 37 publications

(19 citation statements)

References 28 publications

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“…1 In nonerythrocyte tissues, a small intracellular labile pool of nonheme-and nonferritin-bound LMW-Fe 2ϩ is maintained for incorporation into iron-containing proteins by a poorly characterized regulatory process that is sensitive to intracellular redox state and cellular iron stores. 1,20 This pool of intracellular LMW-Fe 2ϩ is exchangeable with ferritin-bound iron, is readily chelatable, and is accessible as a catalyst for the production of hydroxyl radical in the Fenton reaction. 14,[21][22][23] The hydroxyl radical is a highly reactive species that leads to lipid peroxidation, oxidative damage of DNA, cell dysfunction, and death.…”

Section: Iron-based Oxidative Stressmentioning

confidence: 99%

Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects

Zheng

Dimayuga

Hudaihed

et al. 2002

ATVB

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Objective-Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. Methods and Results-Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of L-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m 2 ) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1Ϯ0.4 mol/L at baseline to 14.2Ϯ1.3 mol/L at 4 hours, PϽ0.001) and decreased FMD (from 3.8Ϯ0.7% at baseline to 1.2Ϯ0.5% at 4 hours, Pϭ0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9Ϯ1.1 mol/L at 4 hours, Pϭ0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5Ϯ0.5% at baseline to 5.9Ϯ1.1% at 4 hours, PϽ0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane. Key Words: methionine Ⅲ vascular endothelium Ⅲ oxidative stress Ⅲ chelation Ⅲ iron L ow molecular weight ferrous iron (LMW-Fe 2ϩ ) catalyzes the production of hydroxyl radicals from hydrogen peroxide in the Fenton reaction. 1 The hydroxyl radical is a highly reactive species that leads to lipid peroxidation, oxidative damage of DNA, cell dysfunction, and death. 2 Dexrazoxane (ICFR-187), a cyclic derivative of the chelating agent EDTA, is approved by the Federal Drug Administration for the prevention of anthracycline cardiotoxicity in humans. In contrast to EDTA and deferoxamine, dexrazoxane is membrane permeable and chelates LMW-Fe 2ϩ in the intracellular space, where hydrolysis of 2 imide bonds activates its binding sites. 3 The cardioprotective action of dexrazoxane is due to its high-affinity binding of intracellular LMW-Fe 2ϩ , which reduces the formation of anthracycline-iron complexes and the consequent generation of hydroxyl radical and other toxic reactive oxygen species. 4,5 Hyperhomocysteinemia induced by oral methionine ingestion in normal subjects is associated with increased oxidant stress and transient vascular endothelial dysfunction. 6 -8 The present study was undertaken to test the hypothesis that the antioxidant effects of dexrazoxane would prevent vascular endothelial dysfunction induced by homocysteine in the brachial artery of normal human subjects in a double-blind, placebo-controlled, crossover study. Methods Study PopulationEight men and 2 women were studied. All subjects were normotensive nonsmokers with no history of chronic illness or chronic medication use. Criteria for exclusion were LDL Ͼ160 mg/dL, fasting blood sugar Ͼ110 mg/dL, plasma homocysteine Ͼ10 mol/L, an...

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Section: Iron-based Oxidative Stressmentioning

confidence: 99%

Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects

Zheng

Dimayuga

Hudaihed

et al. 2002

ATVB

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“…In particular, a number of studies have described metabolic conversion of ethanol through induction of cytochrome P450 2E1 (CYP2E1) [71,100]. Although CYP2E1 is present in low levels in the CNS [30,94], induction of this enzyme together with increased ROS production has been reported in rats after chronic ethanol administration [59].…”

Section: Ethanol and Oxidative Stress In The Brainmentioning

confidence: 99%

Ethanol and Oxidative Mechanisms in the Brain

Sun

2001

J Biomed Sci

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There is strong evidence showing that chronic and excessive ethanol consumption may enhance oxidative damage to neurons and result in cell death. Although not yet well understood, ethanol may enhance ROS production in brain through a number of pathways including increased generation of hydroxyethyl radicals, induction of CYP2E1, alteration of the cytokine signaling pathways for induction of iNOS and sPLA₂, and production of prostanoids through the PLA₂/COX pathways. Since many neurodegenerative diseases are also associated with oxidative and inflammatory mechanisms in the brain, it would be important to find out whether chronic and excessive ethanol consumption may exacerbate the progression of these diseases. There is evidence that the polyphenolic antioxidants, especially those extracted from grape skin and seed, may protect the brain from neuronal damage due to chronic ethanol administration. Among the polyphenols from grapes, resveratrol seems to have unique antioxidant properties. The possible use of this compound as a therapeutic agent to ameliorate neurodegenerative processes should be further explored.

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“…Superoxide may be formed via a number of mechanisms including formation from cytochrome P450 (Puntarulo and Cederbaum, 1996) and other enzymes. We evaluated the importance of activation of Kupffer cells, macrophages, or neutrophils (the so-called respiratory burst) in acetaminophen toxicity.…”

Section: Superoxide Formation and Mitochondrial Dysfunction In Acetammentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity

James¹,

Mayeux²,

Hinson³

2003

Drug Metab Dispos

878

670

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1␤ is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.

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Role of cytochrome P-450 in the stimulation of microsomal production of reactive oxygen species by ferritin

Cited by 37 publications

References 28 publications

Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects

Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects

Ethanol and Oxidative Mechanisms in the Brain

Acetaminophen-Induced Hepatotoxicity

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