In vivo evidence for accelerated generation of hydroxyl radicals in liver of Long-Evans Cinnamon (LEC) rats with acute hepatitis

Yamamoto, Hideki; Watanabe, Tomohiro; Mizuno, Hatsue; Endo, Kazuo; Hosokawa, Tsunemichi; Kazusaka, Akio; Gooneratne, Ravi; Fujita, Shoichi

doi:10.1016/s0891-5849(00)00496-2

Cited by 53 publications

(37 citation statements)

References 39 publications

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“…SA and 2,3-DHBA were measured according to the methods of Tsai et al (1998) and Yamamoto et al (2001) respectively, both with modifications. For the determination of SA and 2,3-DHBA, tissue samples (within 0 .…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Hyperglycemia induces apoptosis in rat liver through the increase of hydroxyl radical: new insights into the insulin effect

Francés

Ronco²,

Monti³

et al. 2010

Journal of Endocrinology

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In this study, we analyzed the contribution of hydroxyl radical in the liver apoptosis mediated by hyperglycemia through the Bax-caspase pathway and the effects of insulin protection against the apoptosis induced by hyperglycemia. Male adult Wistar rats were randomized in three groups: control (C) (sodium citrate buffer, i.p.), streptozotocin (STZ)-induced diabetic (SID) (STZ 60 mg/kg body weight, i.p.), and insulintreated SID (SIDCI; 15 days post STZ injection, SID received insulin s.c., twice a day, 15 days). Rats were autopsied on day 30. In liver tissue, diabetes promoted a significant increase in hydroxyl radical production which correlated with lipid peroxidation (LPO) levels. Besides, hyperglycemia significantly increased mitochondrial BAX protein expression, cytosolic cytochrome c levels, and caspase-3 activity leading to an increase in apoptotic index. Interestingly, the treatment of diabetic rats with desferoxamine or tempol (antioxidants/ hydroxyl radical scavengers) significantly attenuated the increase in both hydroxyl radical production and in LPO produced by hyperglycemia, preventing apoptosis by reduction of mitochondrial BAX and cytosolic cytochrome c levels. Insulin treatment showed similar results. The finding that co-administration of antioxidants/hydroxyl radical scavengers together with insulin did not provide any additional benefit compared with those obtained using either inhibitors or insulin alone shows that it is likely that insulin prevents oxidative stress by reducing the effects of hydroxyl radicals. Importantly, insulin significantly increased apoptosis inhibitor protein expression by induction of its mRNA. Taken together, our studies support that, at least in part, the hydroxyl radical acts as a reactive intermediate, which leads to liver apoptosis in a model of STZ-mediated hyperglycemia. A new anti-apoptosis signal for insulin is shown, given by an increase of apoptosis inhibitor protein.

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Section: Animals and Treatmentsmentioning

confidence: 99%

Hyperglycemia induces apoptosis in rat liver through the increase of hydroxyl radical: new insights into the insulin effect

Francés

Ronco²,

Monti³

et al. 2010

Journal of Endocrinology

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“…This copper, together with iron, seems to damage the lysosomes via oxidation, resulting in hepatocyte necrosis (Klein et al 1998, Yamamoto et al 2001. Subsequent to phagocytosis by Kupffer cells, accumulated reactive copper may amplify liver damage either directly or indirectly through stimulation of the Kupffer cells (Klein et al 1998).…”

Section: Volume 22mentioning

confidence: 99%

Copper and its inorganic compounds [MAK Value Documentation, 2006]

2012

The MAK‐Collection for Occupational Health and Safety

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Published in the series MAK Value Documentations , Vol. 22 (2006) The article contains sections titled: Toxic Effects and Mode of Action Mechanism of Action Toxicokinetics and Metabolism Effects in Humans Single exposures Repeated exposures Local effects on skin and mucous membranes Allergenic effects Reproductive toxicity Carcinogenicity Animal experiments and in vitro studies Acute toxicity Subacute, subchronic and chronic toxicity Local effects on skin and mucous membranes Allergenic effects Reproductive toxicity Genotoxicity Carcinogenicity Other effects Manifesto (MAK value/classification)

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“…The Long-Evans Cinnamon (LEC) rat strain, which accumulates copper in the liver due to mutations in the Atp7b gene, has been used as a model to investigate the relationship between oxidative stress and hepatocarcinogenesis (5)(6)(7)(8)(9)(10)(11). The hepatic levels of oxidative stress indicators in LEC rats were found to be elevated during the onset of fulminant hepatitis between 16 and 24 weeks of age, while the levels of antioxidants such as ascorbate and ubiquinol were concomitantly decreased.…”

Section: Introductionmentioning

confidence: 99%

Aldo-keto reductase 1 family B7 is the gene induced in response to oxidative stress in the livers of Long-Evans Cinnamon rats

Chen

Takahashi²,

Zhang³

et al. 2006

Int J Oncol

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Abstract. The Long-Evans Cinnamon (LEC) rat strain (Atp7b m/m), which accumulates copper in the liver due to mutations in the Atp7b gene, is a useful model for investigating the relationship between oxidative stress and hepatocarcinogenesis. To determine the effect of this mutation on oxidative stress marker genes, we performed oligonucleotide array analysis (Affymetrix), and compared the results in Atp7b m/m rats with those of a sibling line with the Atp7b w/w genotype. We focused our studies on the expression of the aldo-keto reductase 1 family B7 (AKR1B7)-like protein gene, since this gene codes for reductase enzymes involved in the detoxification of oxidizing compounds (e.g., aldehydes) and was differentially expressed in Atp7b m/m and Atp7b w/w rat liver. Akr1B7 mRNA expression was significantly increased in comparison with the expression of 4 other known oxidative stress responsive genes, haem-oxygenase-1 (HO-1), thioredoxin (Trx), aldehyde reductase (AKR1A1), and glucose-6-phosphate dehydrogenase (G6PDH). By searching binding motifs, five nuclear factor kappa B (NF-κB) binding sites were located in the 5'-upstream region of the Akr1b7 gene. Transient co-transfection with both I-κB· and the Akr1b7 6 kb promoter (p6.0-AKR-Luc) inhibited luciferase activity of p6.0-AKR-Luc in HepG2 cells. Cuprous ion however did not affect the transcription activity induced by p6.0-AKR-Luc. Gel-shift assay showed that the DNA binding activity of NF-κB increased in the livers of LEC rats, suggesting that the oxidative stress is mediated through NF-κB. The results indicate conclusively that in LEC rat liver, Akr1b7 might be up-regulated by oxidative stress mediated through NF-κB, but not that mediated directly by copper. IntroductionHepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and one of the most deadly cancers with approximately 600,000 yearly deaths (1). Hepatocarcinogenesis is a multi-step process and cellular oxidative stress is one of the factors responsible for the propagation of liver diseases, such as hepatitis, cirrhosis, and hepatoma (2-4). Although much is known about the cellular pathogenesis and etiological agents leading to HCC, the molecular events are not well understood. Recent advances in genomics and proteomics have had the potential to identify characteristics of HCC that may be related to prognosis or to etiology, and these may be useful in HCC screening or diagnosis. Here the Long-Evans Cinnamon (LEC) rat model provides a unique opportunity to unveil the early molecular event associated with oxidative stress-related hepatocarcinogenesis.The Long-Evans Cinnamon (LEC) rat strain, which accumulates copper in the liver due to mutations in the Atp7b gene, has been used as a model to investigate the relationship between oxidative stress and hepatocarcinogenesis (5-11). The hepatic levels of oxidative stress indicators in LEC rats were found to be elevated during the onset of fulminant hepatitis between 16 and 24 weeks of age, while the levels of antioxidants such as ascorbate and ubi...

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In vivo evidence for accelerated generation of hydroxyl radicals in liver of Long-Evans Cinnamon (LEC) rats with acute hepatitis

Cited by 53 publications

References 39 publications

Hyperglycemia induces apoptosis in rat liver through the increase of hydroxyl radical: new insights into the insulin effect

Hyperglycemia induces apoptosis in rat liver through the increase of hydroxyl radical: new insights into the insulin effect

Copper and its inorganic compounds [MAK Value Documentation, 2006]

Aldo-keto reductase 1 family B7 is the gene induced in response to oxidative stress in the livers of Long-Evans Cinnamon rats

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