Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma

Jüngst, Christoph; Cheng, Bin; Gehrke, Ralph; Schmitz, Volker; Nischalke, Hans Dieter; Ramakers, J.J.M.; Schramel, P.; Schirmacher, Peter; Sauerbruch, Tilman; Caselmann, Wolfgang H.

doi:10.1002/hep.20241

Cited by 115 publications

(73 citation statements)

References 41 publications

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“…During inflammation, infiltration of activated phagocytic cells provides a source of ROS production and therefore promotes oxidative stress and damage to proteins, lipids, and DNA [27]. Here, we further showed the importance of HBx and mitochondria in HBV-infected liver cells as an additional source for ROS and inflammatory signaling.…”

Section: Discussionsupporting

confidence: 58%

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBx Δ68-117 ) neither increased intracellular ROS levels nor induced COX-2 expression. HBx 68-117 , which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calciumdependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.

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Section: Discussionsupporting

confidence: 58%

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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“…Increasing evidence points to free-radical damage as an important contributor to the diseases [22,23]. Several host mechanisms are in place to neutralize the harmful effect of free radicals; these include a system of nutritional and endogenous enzymatic antioxidant defences that generally restrain the production of free radicals and prevent oxidant stress and subsequent tissue damage [24].…”

Section: Discussionmentioning

confidence: 99%

Antioxidant status and lipid peroxidation activity in evaluating hepatocellular damage in children

Mahdy¹,

Abd-El-Shaheed²,

Khadr³

et al. 2009

East Mediterr Health J

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Serum levels of glutathione reductase (GR), glutathione S-transferase-α (GST-α) and malondialdehyde (MDA) were determined to evaluate their use in diagnosing hepatocellular damage in 75 children with liver disease. Except for level of GR in patients with HBV, GR, GST-α and MDA were raised significantly in patients compared with controls. At 100% specificity, the sensitivity of the 3 markers for detecting hepatitis B virus, hepatitis C virus and schistosomiasis infection respectively were: 16.7%, 100.0% and 17.7% for GR; 33.3%, 62.1% and 38.2% for GST-α; and 25.0%, 10.3% and 29.4% for MDA. GR was more sensitive in hepatitis C infection, while MDA reflected changes in liver ultrasound and GST-α was the best indicator for histopathological changes. Rôle du statut antioxydant et du processus de péroxydation des lipides dans l'évaluation des lésions hépatocellulaires chez l'enfant RÉSUMÉ Nous avons déterminé les taux sériques de glutathion-réductases (GR), d'α-glutathion-Stransférases (α-GST) et de malondialdéhyde (MDA) afin d'évaluer leur rôle dans le diagnostic des lésions hépatocellulaires chez 75 enfants souffrant d'une maladie hépatique. À l'exception du taux de GR chez les patients atteints du virus de l'hépatite B (VHB), les taux de GR, d'α-GST et de MDA étaient significativement plus élevés chez les malades que chez les témoins. Avec une spécificité de 100 %, la sensibilité des trois marqueurs pour le dépistage du VHB, du VHC et de la schistosomiase était respectivement de 16,7 %, 100,0 % et 17,7 % pour les GR ; de 33,3 %, 62,1 % et 38,2 % pour les α-GST ; et de 25,0 %, 10,3 % et 29,4 % pour le MDA. Les GR étaient plus sensibles dans le cas de l'infection par le VHC, alors que le MDA témoignait de changements à l'échographie du foie et que les α-GST étaient le meilleur indicateur des changements histopathologiques.

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“…Aberrations in methylation and redox homeostasis are common to a number of chronic diseases including pathologies of the liver. In alcoholic liver disease and in hepatocellular carcinoma an increase in markers of oxidative stress is observed (1,2). Furthermore, there is a switch in the expression of MAT genes from MAT1A to MAT2A in liver cancer, which correlates with lower S-adenosylmethionine (AdoMet) levels (3).…”

mentioning

confidence: 99%

S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

Prudova

Bauman

Braun

et al. 2006

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

220

202

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The transsulfuration pathway converts homocysteine to cysteine and represents the metabolic link between antioxidant and methylation metabolism. The first and committing step in this pathway is catalyzed by cystathionine ␤-synthase (CBS), which is subject to complex regulation, including allosteric activation by the methyl donor, S-adenosylmethionine (AdoMet). In this study, we demonstrate that methionine restriction leads to a >10-fold decrease in CBS protein levels, and pulse proteolysis studies reveal that binding of AdoMet stabilizes the protein against degradation by Ϸ12 kcal͞mol. These observations predict that under pathological conditions where AdoMet levels are diminished, CBS, and therefore glutathione levels, will be reduced. Indeed, we demonstrate this to be the case in a mouse model for spontaneous steatohepatitis in which the gene for the MAT1A isoenzyme encoding AdoMet synthetase has been disrupted, and in human hepatocellular carcinoma, where MAT1A is silenced. Furthermore, diminished CBS levels are associated with reduced cell viability in hepatoma cells challenged with tert-butyl hydroperoxide. This study uncovers a mechanism by which CBS is allosterically activated by AdoMet under normal conditions but is destabilized under pathological conditions, for redirecting the metabolic flux toward methionine conservation. A mechanistic basis for the coordinate changes in redox and methylation metabolism that are a hallmark of several complex diseases is explained by these observations. glutathione ͉ liver disease C ellular methylation and antioxidant metabolism are linked by the transsulfuration pathway, which converts the methionine cycle intermediate, homocysteine, to cysteine, the limiting reagent in glutathione synthesis. The balance between conserving methionine via transmethylation under conditions of methionine restriction and committing it to transsulfuration under conditions of plenty is regulated at two key control points, methionine adenosyltransferase (MAT) and cystathionine ␤-synthase (CBS) (Fig. 1). Aberrations in methylation and redox homeostasis are common to a number of chronic diseases including pathologies of the liver. In alcoholic liver disease and in hepatocellular carcinoma an increase in markers of oxidative stress is observed (1, 2). Furthermore, there is a switch in the expression of MAT genes from MAT1A to MAT2A in liver cancer, which correlates with lower S-adenosylmethionine (AdoMet) levels (3).Under normal conditions, coordinate regulation of methylation and antioxidant metabolism is achieved by the allosteric activation of CBS by AdoMet (Fig. 1). AdoMet is a V-type allosteric effector that increases CBS activity 2-to 3-fold (4, 5). Under conditions of plenty, methionine is directed toward cysteine synthesis via the transsulfuration pathway for use in glutathione and other cellular functions or directed toward catabolism. Cysteine is the limiting reagent in glutathione synthesis and in liver; Ϸ50% of the cysteine in glutathione is derived from methionine via the transsulf...

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Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma

Cited by 115 publications

References 41 publications

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Antioxidant status and lipid peroxidation activity in evaluating hepatocellular damage in children

S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

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