Formation of acetaldehyde adducts with ethanol-inducible P450IIE1 in vivo

Behrens, U.; Hoerner, M; Lasker, Jerome M.; Lieber, Charles S.

doi:10.1016/0006-291x(88)90180-5

Cited by 137 publications

(56 citation statements)

References 23 publications

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“…Our observations strongly suggest that APA formation occurs locally at the sites of acetaldehyde production, since cytosol, rough endoplasmic reticulum, and peroxisomes correspond to the three sites of acetaldehyde production in hepatocytes, through, respectively, alcohol dehydrogenase, the microsomal ethanol oxidizing system (MEOS), and peroxisomal catalase (Lieber, 1991). It is noteworthy that cytochrome P450-IIE1, an inducible enzyme which is part of the MEOS found in microsomes, and a yet undefined 37-KD protein located in the cytosol have already been shown to form APAs in other studies (Lin and Lumeng, 1989;Behrens et al, 1988). Proteins that can form APAs in the peroxisomes have not been yet identified.…”

Section: Discussionmentioning

confidence: 94%

Cellular and subcellular localization of acetaldehyde-protein adducts in liver biopsies from alcoholic patients.

Paradis

Scoazec²,

Köllinger³

et al. 1996

J Histochem Cytochem.

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Acetaldehyde, the first product of ethanol in hepatocytes, can react with protein to form acetaldehyde-protein adducts (APAs). Because it has been suggested that these adducts could be involved in the pathogenesis of ethanol-induced hepatic lesions and in fibrogenesis, we performed an ultrastructural immunohistochemical study to precisely define the cellular and subcellular localization of APAs. A preembedding technique of indirect immunoperoxidase was performed in liver biopsy specimens from eight patients with alcoholic liver disease, using a specific antiserum against APAs. In all specimens, APAs were detected in the rough endoplasmic reticulum, in some peroxisomes, and in the cytosol of hepatocytes. In four patients with steatofibrosis or cirrhosis, labeling of Ito cells was also observed. In these cases, the same staining pattern was observed in the cytoplasmic processes of myofibroblasts in areas of fibrogenesis. When isolated rat Ito cells were incubated in the presence of acetaldehyde, APAs were also detected in the cytoplasm. These results show that APA formation occurs in hepatocytes at the sites of acetaldehyde production. Detection of APAs in human and rat Ito cells strongly suggests that acetaldehyde can diffuse into Ito cells and bind to cytoplasmic proteins to form local APAs. Because Ito cells are the main effector cells of liver fibrosis, detection of APAs in these cells points to their possible involvement in liver fibrogenesis.

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Section: Discussionmentioning

confidence: 94%

Cellular and subcellular localization of acetaldehyde-protein adducts in liver biopsies from alcoholic patients.

Paradis

Scoazec²,

Köllinger³

et al. 1996

J Histochem Cytochem.

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“…Acetaldehyde generated during alcohol consumption forms adducts with liver proteins, including the 37 kd and several additional liver proteins reported by other investigators. [4][5][6][7][8][9] The modification of ⌬ 4 -3-ketosteroid-5␤ reductase by acetaldehyde in vivo inhibits its enzyme activity, which leads to an accumulation of HCO in the pericentral area of the liver and causes cell necrosis locally. Stellate cells, also termed Ito cells or lipocytes, are the principal cell population in the liver that, when activated, synthesize collagen during fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Acetaldehyde is highly reactive and forms adducts with proteins in vitro and in vivo. Although the in vivo formation of adducts between acetaldehyde and hepatic proteins has been well documented both in alcoholfed rats and in human alcoholic patients, [3][4][5][6][7][8][9] whether any of these liver protein-acetaldehyde adducts is involved in the pathogenesis of alcoholic liver disease (ALD) remains unclear.…”

mentioning

confidence: 99%

Cytotoxic effect of 7α-hydroxy-4-cholesten-3-one on HepG2 cells: Hypothetical role of acetaldehyde-modified Δ4-3-ketosteroid-5β-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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“…Binding of this ethanol metabolite to these enzymes, forming a stable adduct, can impair their properties [35]. Thus, it is possible that the P-450 l lEl enzyme induced by ethanol is malfunctioning [58]. The extent to which acetaldehyde found within the brain after ethanol dosing, is generated intrinsically rather than systemically transported from the liver, is unclear.…”

Section: Non-enzymic Reaction Of Acetaldehyde With Proteinsmentioning

confidence: 99%

Exposure of mice to tobacco smoke attenuates the toxic effect of methamphetamine on dopamine systems

2000

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SUMMARY 231The mechanisms underlying the toxicity of ethanol have been the subject of much study, but are not well understood. Unlike many selective pharmacological agents, ethanol clearly has several major loci of action. One deleterious factor in ethanol metabolism is the potential for generation of excess amounts of free radicals. The extent to which this activity accounts for the overall toxicity of ethanol is unknown. This review outlines the enzymic steps that have the capacity to generate reactive oxygen species. These steps are likely to differ in acute and extended exposures to ethanol. Acetaldehyde catabolism also has the likelihood of contributing to ethanol-related oxidative stress. The review focuses on the ethanol-induced production of excess amounts of pro-oxidant reactive species in both the liver and the central nervous system. The potential of various stages of ethanol catabolism to involve generation of free radicals is described.

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Formation of acetaldehyde adducts with ethanol-inducible P450IIE1 in vivo

Cited by 137 publications

References 23 publications

Cellular and subcellular localization of acetaldehyde-protein adducts in liver biopsies from alcoholic patients.

Cellular and subcellular localization of acetaldehyde-protein adducts in liver biopsies from alcoholic patients.

Cytotoxic effect of 7α-hydroxy-4-cholesten-3-one on HepG2 cells: Hypothetical role of acetaldehyde-modified Δ4-3-ketosteroid-5β-reductase (the 37-kd-liver protein) in the pathogenesis of alcoholic liver injury in the rat

Exposure of mice to tobacco smoke attenuates the toxic effect of methamphetamine on dopamine systems

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