Metallothionein Protection against Alcoholic Liver Injury through Inhibition of Oxidative Stress

Antioxidants are likely potential pharmaceutical agents for the treatment of alcoholic liver disease. Metallothionein (MT) is a cysteine-rich protein and functions as an antioxidant. This study was designed to determine whether MT confers resistance to acute alcohol-induced hepatotoxicity and to explore the mechanistic link between oxidative stress and alcoholic liver injury. MT-overexpressing transgenic and wild-type mice were administrated three gastric doses of alcohol at 5 g/kg. Liver injury, oxidative stress, and ethanol metabolism-associated changes were determined. Acute ethanol administration in the wild-type mice caused prominent microvesicular steatosis, along with necrosis and elevation of serum alanine aminotransferase. Ultrastructural changes of the hepatocytes include glycogen and fat accumulation, organelle abnormality, and focal cytoplasmic degeneration. This acute alcohol hepatotoxicity was significantly inhibited in the MT-transgenic mice. Furthermore, ethanol treatment decreased hepatic-reduced glutathione, but increased oxidized glutathione along with lipid peroxidation, protein oxidation, and superoxide generation in the wild-type mice. This hepatic oxidative stress was significantly suppressed in the MT-transgenic mice. However, MT did not affect the ethanol metabolism-associated decrease in NAD+/NADH ratio or increase in cytochrome P450 2E1. In conclusion, MT is an effective agent in cytoprotection against alcohol-induced liver injury, and hepatic protection by MT is likely through inhibition of alcohol-induced oxidative stress.

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Hepatoprotective effects of chamazulene against alcohol-induced liver damage by alleviation of oxidative stress in rat models

Open Life Sciences ◽

10.1515/biol-2020-0026 ◽

2020 ◽

Vol 15 (1) ◽

pp. 251-258

Author(s):

Xu Wang ◽

Ke Dong ◽

Yujing Ma ◽

Qizhi Jin ◽

Shujun Yin ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Serum Alkaline Phosphatase ◽

Positive Control ◽

Ethanol Administration ◽

Control Group ◽

Protective Effects ◽

Alcoholic Liver Injury ◽

Rat Models ◽

Hepatoprotective Effects

AbstractLiver injury and disease caused by alcohol is a common complication to human health worldwide. Chamazulene is a natural proazulene with antioxidant and anti-inflammatory properties. This study aims to investigate the hepatoprotective effects of chamazulene against ethanol-induced liver injury in rat models. Adult Wistar rats were orally treated with 50% v/v ethanol (8–12 mL/kg body weight [b.w.]) for 6 weeks to induce alcoholic liver injury. Chamazulene was administered orally to rats 1 h prior to ethanol administration at the doses of 25 and 50 mg/kg b.w. for 6 weeks. Silymarin, a commercial drug for hepatoprotection, was orally administered (50 mg/kg b.w.) for the positive control group. Chamazulene significantly reduced (p < 0.05) the levels of serum alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and malondialdehyde, whereas the levels of antioxidant enzymes (glutathione peroxidase, catalase, and superoxide dismutase) and reduced glutathione were significantly restored (p < 0.05) in contrast to the ethanol model group. The levels of pro-inflammatory cytokines (tumour necrosis factor-α and interleukin-6) were suppressed by chamazulene (p < 0.05) with relevance to ethanol-induced liver injury. Histopathological alterations were convincing in the chamazulene-treated groups, which showed protective effects against alcoholic liver injury. Chamazulene has a significant hepatoprotective effect against ethanol-induced liver injury through alleviation of oxidative stress and prevention of inflammation.

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Escherichia coli MutM Suppresses Illegitimate Recombination Induced by Oxidative Stress

Genetics ◽

10.1093/genetics/151.2.439 ◽

1999 ◽

Vol 151 (2) ◽

pp. 439-446 ◽

Cited By ~ 2

Author(s):

Masaaki Onda ◽

Katsuhiro Hanada ◽

Hirokazu Kawachi ◽

Hideo Ikeda

Keyword(s):

Oxidative Stress ◽

Escherichia Coli ◽

Hydrogen Peroxide ◽

Dna Damage ◽

Double Strand Breaks ◽

Illegitimate Recombination ◽

Recombination Analysis ◽

Wild Type ◽

Strand Breaks ◽

In The Wild

Abstract DNA damage by oxidative stress is one of the causes of mutagenesis. However, whether or not DNA damage induces illegitimate recombination has not been determined. To study the effect of oxidative stress on illegitimate recombination, we examined the frequency of λbio transducing phage in the presence of hydrogen peroxide and found that this reagent enhances illegitimate recombination. To clarify the types of illegitimate recombination, we examined the effect of mutations in mutM and related genes on the process. The frequency of λbio transducing phage was 5- to 12-fold higher in the mutM mutant than in the wild type, while the frequency in the mutY and mutT mutants was comparable to that of the wild type. Because 7,8-dihydro-8-oxoguanine (8-oxoG) and formamido pyrimidine (Fapy) lesions can be removed from DNA by MutM protein, these lesions are thought to induce illegitimate recombination. Analysis of recombination junctions showed that the recombination at Hotspot I accounts for 22 or 4% of total λbio transducing phages in the wild type or in the mutM mutant, respectively. The preferential increase of recombination at nonhotspot sites with hydrogen peroxide in the mutM mutant was discussed on the basis of a new model, in which 8-oxoG and/or Fapy residues may introduce double-strand breaks into DNA.

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A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production

Journal of Nutritional Science ◽

10.1017/jns.2016.43 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 16

Author(s):

Ryusei Uchio ◽

Yohei Higashi ◽

Yusuke Kohama ◽

Kengo Kawasaki ◽

Takashi Hirao ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Oral Administration ◽

Alanine Aminotransferase ◽

Curcuma Longa ◽

Water Extract ◽

Hot Water ◽

Hepatic Tissue ◽

Hot Water Extract ◽

Acute Ethanol

AbstractTurmeric (Curcuma longa) is a widely used spice that has various biological effects, and aqueous extracts of turmeric exhibit potent antioxidant activity and anti-inflammatory activity. Bisacurone, a component of turmeric extract, is known to have similar effects. Oxidative stress and inflammatory cytokines play an important role in ethanol-induced liver injury. This study was performed to evaluate the influence of a hot water extract of C. longa (WEC) or bisacurone on acute ethanol-induced liver injury. C57BL/6 mice were orally administered WEC (20 mg/kg body weight; BW) or bisacurone (60 µg/kg BW) at 30 min before a single dose of ethanol was given by oral administration (3·0 g/kg BW). Plasma levels of aspartate aminotransferase and alanine aminotransferase were markedly increased in ethanol-treated mice, while the increase of these enzymes was significantly suppressed by prior administration of WEC. The increase of alanine aminotransferase was also significantly suppressed by pretreatment with bisacurone. Compared with control mice, animals given WEC had higher hepatic tissue levels of superoxide dismutase and glutathione, as well as lower hepatic tissue levels of thiobarbituric acid-reactive substances, TNF-α protein and IL-6 mRNA. These results suggest that oral administration of WEC may have a protective effect against ethanol-induced liver injury by suppressing hepatic oxidation and inflammation, at least partly through the effects of bisacurone.

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Biphasic effect of acute ethanol administration on rat liver tyrosine-2-oxoglutarate aminotransferase activity

Biochemical Journal ◽

10.1042/bj1860755 ◽

1980 ◽

Vol 186 (3) ◽

pp. 755-761 ◽

Cited By ~ 5

Author(s):

A A B Badawy ◽

B M Snape ◽

M Evans

Keyword(s):

Enzyme Activity ◽

Rat Liver ◽

Actinomycin D ◽

Tyrosine Aminotransferase ◽

Ethanol Metabolism ◽

Ethanol Administration ◽

Aminotransferase Activity ◽

Biphasic Effect ◽

Initial Decrease ◽

Acute Ethanol

1. Acute ethanol administration causes a biphasic change in rat liver tyrosine aminotransferase activity. 2. The initial decrease is significant with a 200 mg/kg dose of ethanol, is prevented by adrenoceptor-blocking agnets and by reserpine, but not by inhibitors of ethanol metabolism, and exhibits many of the characteristics of the inhibition caused by noradrenaline. 3. The subsequent enhancement of the enzyme activity by ethanol is not associated with stabilization of the enzyme, but is sensitive to actinomycin D and cycloheximide. 4. It is suggested that the initial decrease in aminotransferase activity is caused by the release of catecholamines, whereas the subsequent enhancement may be related to the release of glucocorticoids.

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Aloin protects against chronic alcoholic liver injury via attenuating lipid accumulation, oxidative stress and inflammation in mice

Archives of Pharmacal Research ◽

10.1007/s12272-014-0370-0 ◽

2014 ◽

Vol 37 (12) ◽

pp. 1624-1633 ◽

Cited By ~ 21

Author(s):

Yan Cui ◽

Qing Ye ◽

Heya Wang ◽

Yingchao Li ◽

Xiuhua Xia ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Lipid Accumulation ◽

Alcoholic Liver Injury ◽

Chronic Alcoholic

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Acute ethanol pretreatment increases FAS-mediated liver injury in mice: Role of oxidative stress and CYP2E1-dependent and -independent pathways

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2006.12.023 ◽

2007 ◽

Vol 42 (7) ◽

pp. 971-984 ◽

Cited By ~ 21

Author(s):

Xiaodong Wang ◽

Arthur I. Cederbaum

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Acute Ethanol ◽

Ethanol Pretreatment

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Metallothionein protects against alcoholic liver injury in mice through inhmition of oxidative stress

Gastroenterology ◽

10.1016/s0016-5085(00)85833-3 ◽

2000 ◽

Vol 118 (4) ◽

pp. A924

Author(s):

Xiuhui Zhong ◽

Zhanxiang Zhou ◽

Y. James Kang

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Alcoholic Liver Injury

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Increased sensitivity to oxidative injury in chinese hamster ovary cells stably transfected with rat liver S-adenosylmethionine synthetase cDNA

Biochemical Journal ◽

10.1042/bj3190767 ◽

1996 ◽

Vol 319 (3) ◽

pp. 767-773 ◽

Cited By ~ 28

Author(s):

Estrella SÁNCHEZ-GÓNGORA ◽

John G. PASTORINO ◽

Luis ALVAREZ ◽

María A. PAJARES ◽

Concepción GARCÍA ◽

...

Keyword(s):

Oxidative Stress ◽

Rat Liver ◽

Chinese Hamster Ovary ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Wild Type ◽

Ovary Cells ◽

Transfected Cells ◽

In The Wild ◽

Adenosylmethionine Synthetase

Chinese hamster ovary cells were stably transfected with rat liver S-adenosylmethionine synthetase cDNA. As a result, S-adenosylmethionine synthetase activity increased 2.3-fold, an effect that was accompanied by increased S-adenosylmethionine, a depletion of ATP and NAD levels, elevation of the S-adenosylmethionine/S-adenosylhomocysteine ratio (the methylation ratio), increased DNA methylation and polyamine levels (spermidine and spermine), and normal GSH levels. By contrast, the transfected cells showed normal growth curves and morphology. Exposure to an oxidative stress by the addition of H2O2 resulted in a greater consumption of ATP and NAD in the transfected cells than in the wild-type cells. In turn, cell killing by H2O2 was greater in the transfected cells than in the wild-type cells. This killing of Chinese hamster ovary cells by H2O2 involved the activation of poly(ADP-ribose) polymerase with the resultant loss of NAD and ATP. 3-Aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase, but not the antioxidant N,N´-diphenylphenylenediamine, prevented the killing of Chinese hamster ovary cells by H2O2 and maintained the contents of NAD and ATP. The results of this study indicate that a moderate activation of the synthesis of S-adenosylmethionine leads to ATP and NAD depletion and to a greater sensitivity to cell killing by oxidative stress.

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