Cocarcinogenic effects of alcohol in hepatocarcinogenesis

Stickel, Felix; Schuppan, Detlef; Hahn, Eckart G.; Seitz, Helmut K.

doi:10.1136/gut.51.1.132

Cited by 128 publications

(78 citation statements)

References 97 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…More than 80% of European and US cases of HCC develop in cirrhotic livers (2). The prevalence of chronic liver disease and cirrhosis is approximately 400,000, or 0.15%, in the US.…”

Section: Introductionmentioning

confidence: 99%

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Hanczko¹,

Fernández²,

Doherty³

et al. 2009

J. Clin. Invest.

125

View full text Add to dashboard Cite

Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1 -/-and Taldo1 +/-mice spontaneously developed HCC, and Taldo1 -/-mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1 -/-livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced β-catenin phosphorylation and enhanced c-Jun expression in Taldo1 -/-livers reflected adaptation to oxidative stress. Taldo1 -/-hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1 -/-mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.

show abstract

“…More than 80% of European and US cases of HCC develop in cirrhotic livers (2). The prevalence of chronic liver disease and cirrhosis is approximately 400,000, or 0.15%, in the US.…”

Section: Introductionmentioning

confidence: 99%

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Hanczko¹,

Fernández²,

Doherty³

et al. 2009

J. Clin. Invest.

125

View full text Add to dashboard Cite

show abstract

“…The present review focuses on alcohol-related HCC, with special emphasis on oxidative stress. Other alcohol-related mechanisms promoting the development of HCC are outlined elsewhere (Stickel et al, 2002;Pö schl and Seitz, 2004;Stickel and Seitz, 2004;McKillop and Schrum, 2005).…”

Section: Introductionmentioning

confidence: 99%

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

Seitz

Stickel

2006

Biological Chemistry

278

178

View full text Add to dashboard Cite

Hepatocellular cancer is the fifth most frequent cancer in men and the eighth in women worldwide. Established risk factors are chronic hepatitis B and C infection, chronic heavy alcohol consumption, obesity and type 2 diabetes, tobacco use, use of oral contraceptives, and aflatoxin-contaminated food. Almost 90% of all hepatocellular carcinomas develop in cirrhotic livers. In Western countries, attributable risks are highest for cirrhosis due to chronic alcohol abuse and viral hepatitis B and C infection. Among those with alcoholic cirrhosis, the annual incidence of hepatocellular cancer is 1-2%. An important mechanism implicated in alcohol-related hepatocarcinogenesis is oxidative stress from alcohol metabolism, inflammation, and increased iron storage. Ethanolinduced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis. Chronic alcohol exposure elicits hepatocyte hyperregeneration due to the activation of survival factors and interference with retinoid metabolism. Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA etheno adducts. Finally, chronic alcohol abuse interferes with methyl group transfer and may thereby alter gene expression.

show abstract

“…9 Overexpression of CYP2E1 is of direct importance to human health and is associated with a range of diseases, including diabetes mellitus, alcoholic liver disease, and cancer. [10][11][12] The expression level of CYP2E1 increases significantly in heart tissues in humans under ischemia; mice, rats, and dogs with dilated cardiomyopathy (DCM); and spontaneously hypertensive rats. [13][14][15][16][17][18] The overexpression of CYP2E1 is associated with several cellular markers of oxidative stress, as well as with decreased viability as a result of both necrosis and apoptosis.…”

mentioning

confidence: 99%

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Zhang

et al. 2012

Hypertension

View full text Add to dashboard Cite

Abstract-Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT R141W and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of ␣-myosin heavy chain (MHC)-cTnT R141W ϫCYP2E1-silence double-transgenic mice when compared with the cTnT R141W transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome c, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT R141W transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT R141W or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.

show abstract

Cocarcinogenic effects of alcohol in hepatocarcinogenesis

Cited by 128 publications

References 97 publications

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Contact Info

Product

Resources

About

Cocarcinogenic effects of alcohol in hepatocarcinogenesis

Cited by 128 publications

References 97 publications

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

Contact Info

Product

Resources

About

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice