Characterization of Adducts of Ethanol Metabolites with Cytochrome <i>c</i>

Anni, Helen; Israel, Yedy

doi:10.1111/j.1530-0277.1999.tb04020.x

Cited by 14 publications

(4 citation statements)

References 66 publications

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“…This result was in agreement with RC data, supporting the fact that the mitochondria are direct targets for Ac. In addition to Ac-induced cytochrome c release, Anni and Israel (1999) reported that Ac can form adducts with this mitochondrial protein. This interaction probably affects the interaction of cytochrome c with its partner Fig.…”

Section: Discussionmentioning

confidence: 97%

“…The potential role of Ac in the pathogenesis of the alcoholic liver disease is recognized, in addition to adducts formation with proteins and DNA (Anni and Israel 1999;Brooks and Theruvathu 2005); Ac can damage mitochondria by a process that involves oxidative stress (Olivares et al 1997). Lluis et al (2003) reported that Ac impairs GSH transport in the mitochondria by a mechanism that involves endoplasmic reticulum stress-mediated increase in cholesterol, decreasing mitochondrial GSH levels, which could promote oxidative stress.…”

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confidence: 98%

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Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage

et al. 2009

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Acetaldehyde (Ac), the main metabolite of ethanol oxidation, is a very reactive compound involved in alcohol-induced liver damage. In the present work, we studied the effect of Ac in mitochondria functionality. Mitochondria from Wistar rats were isolated and treated with Ac. Ac decreased respiratory control by 50% which was associated with a decrease in adenosine triphosphate content (28.5%). These results suggested that Ac could be inducing changes in cell redox status. We determined protein oxidation, superoxide dismutase (SOD) activity, and glutathione ratio, indicating that Ac induced an enhanced oxidation of proteins and a decrease in SOD activity (90%) and glutathione/oxidized GSH ratio (36%). The data suggested that Ac-induced oxidative stress mediated by mitochondria dysfunction can lead to cell sensitization and to a second oxidative challenge. We pretreated hepatocytes with Ac followed by treatment with antimycin A, and this experiment revealed a noticeable decrease in cell viability, determined by neutral red assay, in comparison with cells treated with Ac alone. Our data demonstrate that Ac impairs mitochondria functionality generating oxidative stress that sensitizes cells to a second damaging signal contributing to the development of alcoholic liver disease.

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Section: Discussionmentioning

confidence: 97%

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confidence: 98%

Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage

et al. 2009

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“…In a variety of peroxidases and also in myoglobin and leghaemoglobin, the protein after heterolytic O±O bond cleavage contains one oxidizing equivalent on the oxyferryl moiety, while the other is present as an amino-acid radical [10,35,41±45]. In the case of horse heart cytochrome c, it has been shown that multiple protein radicals can result from the reaction with peroxides [36,46,47]. The lack of an easily observable oxyferryl species in cytochrome c-550 might be caused by a fast reduction of this species by an aromatic amino acid in the vicinity of the haem, as already suggested by Barr et al for horse heart cytochrome c [36].…”

Section: The Active Species In the Peroxidase Reaction Of Cytochrome mentioning

confidence: 99%

The peroxidase activity of cytochrome c‐550 from Paracoccus versutus

Diederix¹,

Ubbink²,

Canters³

2001

European Journal of Biochemistry

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Next to their natural electron transport capacities, c-type cytochromes possess low peroxidase and cytochrome P-450 activities in the presence of hydrogen peroxide. These catalytic properties, in combination with their structural robustness and covalently bound cofactor make cytochromes c potentially useful peroxidase mimics. This study reports on the peroxidase activity of cytochrome c-550 from Paracoccus versutus and the loss of this activity in presence of H 2 O 2 . The rate-determining step in the peroxidase reaction of cytochrome c-550 is the formation of a reactive intermediate, following binding of peroxide to the haem iron. The reaction rate is very low compared to horseradish peroxidase (approximately one millionth), because of the poor accessibility of the haem iron for H 2 O 2 , and the lack of a base catalyst such as the distal His of the peroxidases. This is corroborated by the linear dependence of the reaction rate on the peroxide concentration up to at least 1 m H 2 O 2 . Steady-state conversion of a reducing substrate, guaiacol, is preceded by an activation phase, which is ascribed to the build-up of amino-acid radicals on the protein. The inactivation kinetics in the absence of reducing substrate are mono-exponential and shown to be concurrent with haem degradation up to 25 mm H 2 O 2 (pH 8.0). At still higher peroxide concentrations, inactivation kinetics are biphasic, as a result of a remarkable protective effect of H 2 O 2 , involving the formation of superoxide and ferrocytochrome c-550.Keywords: cytochrome c; peroxidase; protein radicals; haem; oxidation.Peroxidases are haem containing enzymes that efficiently catalyse substrate oxidations using hydrogen peroxide [1,2]. Peroxidases can function as catalysts in a variety of oxidation reactions on a broad spectrum of substrates and their potential use is therefore considerable. This is more so because they utilize the`clean' oxidant H 2 O 2 [2]. Unfortunately, peroxidases are prone to inactivation during normal turnover. This inherent instability is poorly understood and it is important to investigate the mechanism of inactivation because it is currently the main restriction to commercial application of peroxidases and peroxidase mimics [2±4].Peroxidase activity is inherent to many haem-proteins besides peroxidases. It has been detected in, e.g. haemoglobins and myoglobins, cytochrome c and microperoxidases [5±10]. The latter are small peptides derived from extensive proteolysis of cytochrome c, which have contained a covalently bound haem moiety [8,11]. In some cases protein modification has resulted in enhanced activity [12±14]. Understanding the peroxidase properties of c-type cytochromes is particularly interesting, because these are very stable proteins that remain highly soluble even under conditions of extreme heat, acidity and basicity. Importantly, the covalent linkage, via thioether bonds, of their haem prosthetic group to the protein matrix prevents dissociation of the catalytic moiety from the protein. These properties render cyto...

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“…The combination of ionizing radiation and ethanol exposure can potentially be extremely toxic to tissues due to heightened oxidative stress. Ethanol and/or radiation exposure induce the production of reactive oxygen species (ROS) (Bailey and Cunningham, 2002;Anni and Israel, 1999;Borek, 2004;Chi et al, 2005;Jianlin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The mechanism of elevated toxicity in HepG2 cells due to combined exposure to ethanol and ionizing radiation

Ogony

Matthews

Anni

et al. 2007

J of Applied Toxicology

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Ethanol and ionizing radiation exposure are independently known to cause tissue damage through various mechanisms. The non-enzymatic and enzymatic metabolism of ethanol, the latter via the cytochrome P(450) 2E1-dependent pathway produces free radicals, which deplete cellular glutathione (GSH). Ionizing radiation exposure has been shown to induce lipid peroxidation, DNA damage, protein oxidation and GSH depletion. It was postulated that cells sensitized by ethanol will be susceptible to additional insult, such as by radiation through increased oxidative stress. In this investigation, cultured liver cells (HepG2, human hepatocellular liver carcinoma) were exposed to ethanol, followed by ionizing radiation. The antioxidant status of the cells was evaluated by an array of techniques. Levels of glutathione, cysteine (CYS), and malondialdehyde (MDA) were measured by HPLC. Activities of antioxidant enzymes, catalase and glutathione reductase (GR) were determined enzymatically. Apoptosis was evaluated by the caspases-3 assay and fluorescence microscopy. The data showed that combined treatment with ethanol and radiation resulted in the lowest levels of GSH, and highest MDA level compared with the control. The catalase activity was lower in the combined exposure groups, when compared with the single agent exposure groups, and the glutathione reductase activity was the highest in the combined exposure groups and lowest in the control. These findings suggest that a combination of ethanol and ionizing radiation results in greater toxicity in vitro through elevated oxidative stress.

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Characterization of Adducts of Ethanol Metabolites with Cytochrome c

Cited by 14 publications

References 66 publications

Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage

Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage

The peroxidase activity of cytochrome c‐550 from Paracoccus versutus

The mechanism of elevated toxicity in HepG2 cells due to combined exposure to ethanol and ionizing radiation

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