Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics

Clot, Paolo; Albano, Emanuele; Eliasson, Erik; Tabone, M.; Aricò, S; Israel, Yedy; Moncada, Claudio; Sundberg, M.

doi:10.1053/gast.1996.v111.pm8698201

Cited by 109 publications

(52 citation statements)

References 4 publications

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“…HERs bind to proteins and form neoantigens (Albano et al, 1993). Antibodies against HER-derived epitopes are detectable in the sera of patients with ALD (Clot et al, 1995(Clot et al, , 1996. Induction of CYP2E1 resulted in ALD in animals, and inhibition of CYP2E1 was associated with an improvement in the damage (Gouillon et al, 2000).…”

Section: Acetaldehydementioning

confidence: 99%

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

Seitz

Stickel

2006

Biological Chemistry

282

178

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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.

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Section: Acetaldehydementioning

confidence: 99%

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

Seitz

Stickel

2006

Biological Chemistry

282

178

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“…According to Niemelä et al, determinants recognized by antibodies directed toward hydroxyethyl radical-derived epitopes mainly involve MDA adducts are present in the liver of ethanol-fed animals before any apparent histological damage and CYP2E1. 25 This does not exclude that superoxide anion released by the NADPH oxidase activity of CYP2E1 26 subsequently colocalize with the area of focal necrosis and fibrosis. 30 Furthermore, Nanji et al have reported might also participate in the generation of hydroxyethyl radicals.…”

mentioning

confidence: 99%

Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol

Albano¹,

Clot²,

Morimoto³

et al. 1996

Hepatology

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254

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In recent years the possible involvement of free radicreased the trapping of hydroxyethyl free radicals in cal mediated oxidative injury in the pathogenesis of liver microsomes incubated in vitro with ethanol. Fur-alcohol-induced liver diseases has received increasing thermore, these inhibitors also greatly reduced the pro-attention.1 Clinical studies have shown that products duction of hydroxyethyl radical-derived epitopes detect-of lipid peroxidation can be detected in the liver and associated with an increase of lipid peroxidation, which Rats fed intragastrically with ethanol developed antiwas detectable both in vitro and in vivo. 6,7 Moreover, bodies reacting with hydroxyethyl radicals-modified proteins and the formation of these antibodies was the treatment of rats with diallyl sulfide (DAS) or phegreatly reduced by DAS and PIC. Taken together these nylethyl isothiocyanate (PIC), which inhibited CYP2E1 results suggest that CYP2E1 plays an important role in expression, strongly decreased lipid peroxidation meathe generation of hydroxyethyl radicals during chronic sured in vitro in liver microsomes as well as in vivo in the plasma of alcohol-fed animals. 10 Interestingly, among these animals a positive correlation was evident Abbreviations: CYP2E1, cytochrome P450 2E1; DAS, diallyl sulfide; PIC, between the histological evidence of liver injury (i.e., phenylethyl isothiocyanate; KLH, keyhole limpet hemocyanin; RSA, rat serum steatosis, inflammation, and necrosis) and the liver albumin; Ig, immunoglobulin; 4-POBN, 4-pyridyl-1-oxide-t-butyl nitrone; CYP2E1 content. bind to microsomal proteins 13 and that these adducts Received April 12, 1995; accepted August 17, 1995. have immunologic properties leading to the production

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“…11,12 We have recently reported that hydroxyethyl free radicals (HER), arising during CYP2E1-mediated ethanol metabolism, alkylate CYP2E1 and that HER-modified CYP2E1 is the main antigen recognized by anti-HER antibodies present in patients with alcoholic cirrhosis. 13 It therefore seems possible that an immune response to HER-CYP2E1 may be one mechanism leading to the development of autoantibodies directed toward epitopes in native CYP2E1.…”

mentioning

confidence: 99%

Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease

et al. 2003

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Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics

Cited by 109 publications

References 4 publications

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

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

Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol

Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease

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