Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption.

Niemelä, Onni; Juvonen, Taw; Parkkila, Seppo

doi:10.1172/jci115141

Cited by 145 publications

(65 citation statements)

References 41 publications

(50 reference statements)

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“…The specificity of the antiserum has been shown earlier. 5,6 Polyclonal guinea-pig antisera against MDA and HNE adducts 21 were generous gifts of Dr. Seppo Ylä-Herttuala (University of Kuopio, Finland). Antisera against MDA-low-density lipoprotein (LDL) were raised by immunizing male guinea pigs with homologous MDA-LDL.…”

Section: Methodsmentioning

confidence: 99%

“…1,[4][5][6] The appearance of aldehyde-protein adducts in zone 3 hepatocytes has been shown to be a typical feature of alcohol-induced liver disease. 5,7,8 Our previous follow-up studies in ethanol-fed micropigs have shown that the formation of aldehyde adducts in the liver coincide with elevation of serum transaminases and progressive histopathology. 7 High levels of reactive aldehydic products in the liver also appear to be associated with activation of fibrogenesis.…”

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confidence: 99%

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Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs

et al. 1999

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To assess possible links between ethanol-induced oxidant stress, expression of hepatic cytochrome P450 (CYP) enzymes, and sex steroid status, we used immunohistochemical methods to compare the generation of protein adducts of acetaldehyde (AA), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) with the amounts of CYP2E1, CYP2A, and CYP3A in the livers of castrated and noncastrated male micropigs fed ethanol for 12 months. In castrated micropigs, ethanol feeding resulted in accumulation of fat, hepatocellular necrosis, inflammation, and centrilobular fibrosis, whereas only minimal histopathology was observed in their noncastrated counterparts. CYP2A and CYP3A were more prominent in the castrated animals than in the noncastrated micropigs. Ethanol feeding increased the hepatic content of all CYP forms. The most significant increases occurred in CYP2E1 and CYP3A in the noncastrated animals and in CYP2E1 and CYP2A in the castrated animals. Ethanol-fed castrated animals also showed the greatest abundance of perivenular adducts of AA, MDA, and HNE. In the noncastrated ethanol-fed micropigs a low expression of each CYP form was associated with scant evidence of aldehyde-protein adducts. Significant correlations emerged between the levels of different CYP forms, protein adducts, and plasma levels of sex steroids. The present findings indicate that the generation of proteinaldehyde adducts is associated with the induction of several cytochrome enzymes in a sex steroid-dependent manner. It appears that the premature, juvenile, metabolic phenotype, as induced by castration, favors liver damage. The present findings should be implicated in studies on the gender differences on the adverse effects of ethanol in the liver.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs

et al. 1999

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“…132,133 Whole-bloodassociated acetaldehyde (WBAA) includes both albumin and haemoglobin adducts, the concentration of the latter being 5±10 times higher than that of adducts with plasma proteins. 134,135 WBAA is affected by both acute and antecedent drinking behaviour; it returns to normal levels within 3 weeks of abstinence.…”

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confidence: 99%

“…136 The haemoglobin±acetaldehyde adduct (HbA1-AcH) is detected in patients with excessive alcohol consumption with sensitivity 25± 50%. 42,133,137,138 In patients admitted to a drug and alcohol rehabilitation unit, sensitivity was reported at 67% and speci®city at 77%, better than GGT, AST or MCV; of these markers, HbA1-AcH was the only one signi®cantly correlated with reported alcohol intake and with the theoretical ability to detect heavy hazardous drinking before the onset of liver damage. 139 Immunoglobulin A (IgA) reactivity with acetaldehyde-modi®ed proteins has been shown to be elevated in both alcoholics and heavy drinkers, but not in social drinkers or patients with non-alcoholic liver disease.…”

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confidence: 99%

Biochemical detection and monitoring of alcohol abuse and abstinence

2001

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The merits and limitations of traditional and new markers for alcohol abuse (and abstinence) are critically examined for detection and monitoring of alcoholics, hazardous drinkers and binge drinkers. The traditional markers discussed include g-glutamyltransferase (GGT), aspartate and alanine aminotransaminases (AST, ALT) and mean corpuscular volume (MCV); new markers include mitochondrial AST, carbohydrate-de®cient transferrin (CDT), serum/urine 5hydroxytryptophol, b-hexosaminidase and acetaldehyde adducts. The strengths and weaknesses of several of the self-reporting screening questionnaires are also explored. No laboratory test is reliable enough on its own to support a diagnosis of alcoholism. Sensitivities and speci®cities vary considerably and depend on the population concerned. GGT continues to remain the test that combines greatest convenience and sensitivity; its diagnostic accuracy can be enhanced by combination with other traditional markers (AST, ALT, MCV). None of the newer markers offers signi®cant advantage, although CDT seems to be better at monitoring patients for increased alcohol consumption or progress towards abstinence.

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“…The formation of the 37 kd-PAA was abrogated by feeding rats an ethanol-containing liquid diet supplemented with pyrazole (an enzyme inhibitor for alcohol dehydrogenase) and was enhanced when plasma acetaldehyde concentrations was increased by supplementing the liquid diet with cyanamide (an enzyme inhibitor for aldehyde dehydrogenase). 12 The liver protein-AAs have been found to be located predominantly in the perivenous area of the liver of alcohol-fed rats 13 and human alcoholic patients 7 by immunohistochemistry. The perivenous localization of PAA is consistent with the prominent site of alcohol-induced hepatic injury.…”

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confidence: 99%

Cytotoxic effect of 7?-hydroxy-4-cholesten-3-one on HepG2 cells: Hypothetical role of acetaldehyde-modified ?4-3-ketosteroid-5?-reductase (the 37-kd-liver protein) in the pathogenesis of alcoholic liver injury in the rat

Lin¹,

Fillenwarth²,

Du³

1998

Hepatology

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We recently identified ⌬ 4 -3-ketosteroid-5␤-reductase as the 37 kd liver protein which is highly susceptible to acetaldehyde modification in rats continuously fed alcohol. The 5␤-reductase is a key enzyme involved in bile acid synthesis. We report here that the ability to degrade 7␣-hydroxy-4-cholesten-3-one (HCO) was lower in the liver cytosol of alcohol-fed rats than in control animals, suggesting an inhibition of the 5␤-reductase enzyme activity by acetaldehyde modification. We also showed that HCO exhibited a time-and concentration-dependent cytotoxicity to HepG2 cells. HCO cytotoxicity was noticeable at a concentration of 2.5 g/mL. When 10 g/mL of HCO was added to confluent cell monolayers, 57% and 37% of cells remained viable after 24 and 48 hours of treatment. The decrease in cell viability was accompanied by an increased lactic dehydrogenase activity in the culture medium. DNA extracted from HCO-treated cells showed no evidence of DNA fragmentation when analyzed by agarose gel electrophoresis. Staining with propidium iodide showed no nuclear condensation in cells. Thus, cell death by HCO treatment was caused by necrosis and not by apoptosis. Various agents, including, serum proteins, hormones, bile acids, antioxidants, Ca ϩϩ -chelators, Fe ϩϩ -chelator, CYP450 inhibitor, adenylate cyclase inhibitor, protease inhibitors, and nitric oxide synthase inhibitor, did not protect against HCO cytotoxicity. We speculate that HCO concentrations may be elevated around the pericentral area in the liver after chronic alcohol ingestion, causing local cell necrosis. The release of cellular contents and protein-acetaldehyde adducts (PAAs) may activate nonparenchymal cells and provoke autoimmune reaction. Thus, the formation of the 37 kd-PAA may play an important role in the initiation of alcoholic liver injury. (HEPATOLOGY 1998;27:100-107.)Alcohol is metabolized in the liver mainly by alcohol dehydrogenase (ADH). 1 With prolonged alcohol consumption, the metabolic pathway through cytochrome P450IIE1 becomes important. 2 Both ADH and CYPIIE1 generate acetaldehyde from ethanol.

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Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption.

Cited by 145 publications

References 41 publications

Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs

Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs

Biochemical detection and monitoring of alcohol abuse and abstinence

Cytotoxic effect of 7?-hydroxy-4-cholesten-3-one on HepG2 cells: Hypothetical role of acetaldehyde-modified ?4-3-ketosteroid-5?-reductase (the 37-kd-liver protein) in the pathogenesis of alcoholic liver injury in the rat

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