Experimental liver cirrhosis induced by alcohol and iron.

Tsukamoto, Hidekazu; Horne, Walter I.; Kamimura, Seiichiro; Niemelä, Onni; Parkkila, Seppo; Ylä‐Herttuala, Seppo; Brittenham, Gary M.

doi:10.1172/jci118077

Cited by 481 publications

(306 citation statements)

References 41 publications

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“…Initial suggestions for a role for CYP2E1 in alcoholic liver injury arose from studies with the intragastric model of ethanol feeding in which prominent induction of CYP2E1 occurs and in which significant liver injury occurs (29)(30)(31). In these models, large increases in microsomal lipid peroxidation have been observed and the ethanol-induced liver pathology has been shown to correlate with CYP2E1 levels and elevated lipid peroxidation (29,30,119,120).…”

Section: Cyp2e1 and Alcohol-induced Liver Injurymentioning

confidence: 99%

“…Thus, alcohol plus polyunsaturated fat was required for the injury to occur. Addition of iron, known to generate OH and promote oxidative stress, to these diets exacerbated the liver injury (31). Importantly, addition of antioxidants such as vitamin E, ebselen, superoxide dismutase (SOD), GSH precursors, prevented the alcoholinduced liver injury (28).…”

Section: Introduction-cytochrome P450 Oxidative Stress and Alcoholimentioning

confidence: 99%

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CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

651

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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Section: Cyp2e1 and Alcohol-induced Liver Injurymentioning

confidence: 99%

Section: Introduction-cytochrome P450 Oxidative Stress and Alcoholimentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

651

534

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“…Therefore, polyunsaturated lipids plus alcohol are needed for the production of liver damage. Iron is known both to produce • OH and to induce liver damage; importantly, addition of iron to these diets exacerbated hepatic damage [12]. Interestingly, administration of antioxidants, such as ebselen, vitamin E, superoxide dismutase (SOD), and precursors of GSH prevented alcohol-induced hepatic damage in rats [8].…”

Section: Alcoholic Liver Disease and Free Radicalsmentioning

confidence: 99%

Role of free radicals in liver diseases

2009

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Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B 1 consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-pbenzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

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“…Iron is also believed to be central in the pathogenesis of ALD, and some reports show iron overload as a predictive indicator of higher mortality [15] , and development of hepatocellular carcinoma [16] . In fact, iron overload and alcohol have a synergistic effect on the production of oxidative stress [17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Iron homeostasis and H63D mutations in alcoholics with and without liver disease

Machado¹,

Ravasco²,

Martins³

et al. 2009

WJG

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AIM:To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS:One hundred and fifty-three heavy drinkers (defined as alcohol consumption > 80 g/d for at least 5 years) were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics (LDA)] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics (NLDA)], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS:Gender ratio was similar in both study groups. LDA patients were older than NLDA patients (52 ± 10 years vs 48 ± 11 years, P = 0.03). One third and one fifth of the study population had serum transferrin saturation (TS) greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS (51 ± 27 vs 36 ± 13, P < 0.001) and ferritin levels (559 ± 607 ng/mL vs 159 ± 122 ng/mL, P < 0.001), and lower total iron binding capacity (TIBC) (241 ± 88 µg/dL vs 279 ± 40 µg/dL, P = 0.001). The odds ratio for having liver disease with TS greater than 45% was 2.20 (95% confidence interval (CI): 1.37-3.54). There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients (0.25 vs 0.16, P = 0.03). LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients (49.5% vs 31.6%, P = 0.02). The odds ratio for LDA in patients with H63D mutation was 1.57 (95% CI: 1.02-2.40). CONCLUSION:The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease, in parallel with an increased frequency of H63D HFE mutation.

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Experimental liver cirrhosis induced by alcohol and iron.

Cited by 481 publications

References 41 publications

CYP2E1 and oxidative liver injury by alcohol

CYP2E1 and oxidative liver injury by alcohol

Role of free radicals in liver diseases

Iron homeostasis and H63D mutations in alcoholics with and without liver disease

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