Acetaminophen Toxicity

Mirochnitchenko, Oleg; Weisbrot-Lefkowitz, Miriam; Reuhl, Kenneth R.; Chen, Laishun; Yang, Chung S.; Inouye, Masayori

doi:10.1074/jbc.274.15.10349

Cited by 109 publications

(40 citation statements)

References 30 publications

(22 reference statements)

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“…Our findings also caution the public that blind antioxidant supplementation in clinic or nutrition may not always be desirable. In line of our view, knockout of GPX1 enhanced mouse brain resistance to the kainic acid-induced epileptic seizure (56), whereas overexpressing GPX1 promoted acetaminophen toxicity to mice (57) and tumorigenesis (58). Likewise, vitamin C was able to induce decomposition of lipid hydroperoxides to endogenous geneotoxins (59).…”

Section: Waf1/cip1mentioning

confidence: 52%

Opposite Roles of Selenium-dependent Glutathione Peroxidase-1 in Superoxide Generator Diquat- and Peroxynitrite-induced Apoptosis and Signaling

Fu¹,

Sies²,

Lei³

2001

Journal of Biological Chemistry

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Oxidative injuries including apoptosis can be induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) in aerobic metabolism. We determined impacts of a selenium-dependent glutathione peroxidase-1 (GPX1) on apoptosis induced by diquat (DQ), a ROS (superoxide) generator, and peroxynitrite (PN), a potent RNS. Hepatocytes were isolated from GPX1 knockout (GPX1؊/؊) or wild-type (WT) mice, and treated with 0.5 mM DQ or 0.1-0.8 mM PN for up to 12 h. Loss of cell viability, high levels of apoptotic cells, and severe DNA fragmentation were produced by DQ in only GPX1؊/؊ cells and by PN in only WT cells. These two groups of cells shared similar cytochrome c release, caspase-3 activation, and p21 WAF1/CIP1 cleavage. Higher levels of protein nitration were induced by PN in WT than GPX1؊/؊ cells. Much less and/or slower cellular GSH depletion was caused by DQ or PN in GPX1؊/؊ than in WT cells, and corresponding GSSG accumulation occurred only in the latter. In conclusion, it is most striking that, although GPX1 protects against apoptosis induced by superoxide-generator DQ, the enzyme actually promotes apoptosis induced by PN in murine hepatocytes. Indeed, GSH is a physiological substrate for GPX1 in coping with ROS in these cells. Reactive oxygen species (ROS)1 and reactive nitrogen species (RNS) are constantly generated in aerobic metabolism and involved in pathogenesis of many diseases (1, 2). Pro-oxidants such as diquat (DQ) also induce cellular production of ROS including superoxide anion (O 2 . ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radical (OH ⅐ ) (3). Peroxynitrite (PN), a potent RNS, may be formed by O 2 . and nitric oxide (NO) at a diffusionlimited rate (4). As PN nitrates a variety of biomolecules (5), formation of nitrotyrosine in proteins is often used to assess its cellular activity (6). Selenium is an essential antioxidant nutrient (7) that has potential in preventing cancer (8), viral infection (9), and chronic disease (10). Among the 18 identified mammalian selenoproteins (11, 12), glutathione peroxidase-1 (EC 1.11.19, GPX1) was the first discovered (13, 14) and the most abundant (15). Using GPX1 knockout mice (GPX1Ϫ/Ϫ) (16), we have demonstrated that GPX1 is the metabolic mediator of body selenium to protect mice against pro-oxidantinduced death and oxidative injuries (17,18). In contrast to such strong evidence for the long-assumed role of GPX1 in coping with ROS in vivo (19), the impact of GPX1 on RNSmediated oxidative stress in various organisms is virtually unknown. Earlier, Sies et al. (20) showed that adding GPX1 in human fibroblast lysates was able to reduce PN to nitrite and thus attenuated the PN-mediated protein nitration in the presence of adequate glutathione (GSH). Because nitration of protein tyrosine residues may impair the tyrosine phosphorylationrelated signaling and function (21), their finding has physiological relevance. However, the metabolic role of GPX1 in intact cells in coping with PN might be different from that in cell lysates, because of a strong rea...

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Section: Waf1/cip1mentioning

confidence: 52%

Opposite Roles of Selenium-dependent Glutathione Peroxidase-1 in Superoxide Generator Diquat- and Peroxynitrite-induced Apoptosis and Signaling

Fu¹,

Sies²,

Lei³

2001

Journal of Biological Chemistry

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“…26) Transgenic mice over-expressing SOD or GSH-Px are protected from the hepatotoxicity of AA. 27) This may be due to the greater efficacy of MLT in scavenging free radicals and also its ability to stimulate antioxidant enzymes, which is not observed with NAC.…”

Section: Resultsmentioning

confidence: 99%

Melatonin Protects on Toxicity by Acetaminophen But Not on Pharmacological Effects in Mice

Kanno

Tomizawa

Hiura

et al. 2006

Biological & Pharmaceutical Bulletin

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“…This oxidation leads to the formation of the high fluorescent molecule 2Ј,7Ј-dichlorofluorescein (41). Because of these properties, the DCFH-DA has been widely used as an intracellular H 2 O 2 probe (13,36,37,39,(42)(43)(44)(45). This lower H 2 O 2 steady-state in pGSOD clones seems to be even more relevant if we take into account that these clones present a decrease in the cellular H 2 O 2 consuming system (Tables 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

Lower intracellular hydrogen peroxide levels in cells overexpressing CuZn-superoxide dismutase

Teixeira

Schumacher

Meneghini

1998

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

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Transfection of V79 Chinese hamster cells produced clones in which CuZn-superoxide dismutase (CuZn-SOD) activities were 2.2-to 3.5-fold higher than in the parental cells. An overall reduction of antioxidant enzyme activities and both total and oxidized glutathione levels had been found in these clones. Aconitase activities in these cells were determined to indirectly measure the O 2 ؊ steady-state levels. As expected, in cells overexpressing CuZn-SOD, both total and cytosolic aconitase activities have increased. Because these clones showed reduced oxidized glutathione contents, it is unlikely that they present higher H 2 O 2 steady-state levels as a consequence of the higher SOD levels. The physiological role of superoxide dismutase (SOD) in aerobic organisms has been discussed since the characterization of its enzymatic activity (1). Many efforts have been made to understand this role and also the mechanisms of the superoxide anion (O 2 Ϫ ) toxicity as reviewed by many authors (2-6).One of the strategies that has been widely used to understand O 2 Ϫ toxicity is the production of SOD overexpressing cell lines, as reviewed elsewhere (7,8). In some cases, the overexpression of SOD in mammalian systems produced a higher sensitivity to reactive oxygen species (9, 10) also observed in bacteria (11,12). This has been attributed to an accumulation of the O 2 Ϫ dismutation product, H 2 O 2 , caused by SOD overexpression (9-11). In fact, there are two reports that show higher H 2 O 2 steady-state levels in CuZn-SOD-overexpressing cells (13,14).However, as proposed by Liochev and Fridovich (3,15), an excess of SOD should decrease the steady-state O 2 Ϫ level without increasing the endogenous formation of H 2 O 2 . They discussed that a more efficient O 2 Ϫ dismutation system would, in fact, prevent the formation of higher stoichiometric H 2 O 2 levels by other reactions. Among them are the formation of 1 mol of H 2 O 2 per mol of O 2 Ϫ in the oxidation of the iron-sulfur clusters of aconitase and other dehydratases-as recently reviewed (4) Ϫ steady-state levels were indirectly determined in CuZn-SOD-overexpressing clones by measuring their aconitase activities. H 2 O 2 steadystate levels in these clones were determined by flow cytometric analysis by using the probe 2Ј,7Ј-dichlorofluorescein diacetate (DCFH-DA). CuZn-SOD-overexpressing clones presented reduced H 2 O 2 steady-state levels, and, interestingly, these reduced H 2 O 2 levels were observed even under oxidative stress. MATERIALS AND METHODSCell Culture. M8 is a clone derived from V79 Chinese hamster lung fibroblast. CuZn-SOD overexpressing clones were obtained as described previously (8). The cells were grown in DMEM, pH 7.0, supplemented with 10% (vol͞vol) fetal calf serum, 472 units of penicillin͞ml, and 94 g of streptomycin͞ml. The cells were cultured in humidified CO 2 ͞ air (1:19) at 37°C. CuZn-SOD overexpressing cells were cultured in the presence of 500 g͞ml geneticin, the antibiotic used to select these clones, except for a 48-h period prior to th...

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Acetaminophen Toxicity

Cited by 109 publications

References 30 publications

Opposite Roles of Selenium-dependent Glutathione Peroxidase-1 in Superoxide Generator Diquat- and Peroxynitrite-induced Apoptosis and Signaling

Opposite Roles of Selenium-dependent Glutathione Peroxidase-1 in Superoxide Generator Diquat- and Peroxynitrite-induced Apoptosis and Signaling

Melatonin Protects on Toxicity by Acetaminophen But Not on Pharmacological Effects in Mice

Lower intracellular hydrogen peroxide levels in cells overexpressing CuZn-superoxide dismutase

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