Microsomal ethanol oxidation in the colonic mucosa of the rat

Seitz, Helmut K.; Bösche, J; Czygan, P.; Veith, S.; Kommerell, B.

doi:10.1007/bf00499078

Cited by 25 publications

(13 citation statements)

References 25 publications

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“…Therefore, the loss of mucosal barrier function and increased gut permeability play a central role in the mechanism of alcoholic tissue injury. Tissues in vivo are simultaneously exposed to ethanol and acetaldehyde due to ubiquitous distribution of alcohol dehydrogenase (ADH)3, CYP2E14 and catalase56, all known to metabolize ethanol into acetaldehyde. Mounting evidence indicates that ethanol metabolism by ADH into acetaldehyde plays a crucial role in alcoholic tissue injury in many organs78910111213.…”

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confidence: 99%

Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers

Samak

Gangwar

Meena

et al. 2016

Sci Rep

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Ethanol is metabolized into acetaldehyde in most tissues. In this study, we investigated the synergistic effect of ethanol and acetaldehyde on the tight junction integrity in Caco-2 cell monolayers. Expression of alcohol dehydrogenase sensitized Caco-2 cells to ethanol-induced tight junction disruption and barrier dysfunction, whereas aldehyde dehydrogenase attenuated acetaldehyde-induced tight junction disruption. Ethanol up to 150 mM did not affect tight junction integrity or barrier function, but it dose-dependently increased acetaldehyde-mediated tight junction disruption and barrier dysfunction. Src kinase and MLCK inhibitors blocked this synergistic effect of ethanol and acetaldehyde on tight junction. Ethanol and acetaldehyde caused a rapid and synergistic elevation of intracellular calcium. Calcium depletion by BAPTA or Ca2+-free medium blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. Diltiazem and selective knockdown of TRPV6 or CaV1.3 channels, by shRNA blocked ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. Ethanol and acetaldehyde induced a rapid and synergistic increase in reactive oxygen species by a calcium-dependent mechanism. N-acetyl-L-cysteine and cyclosporine A, blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. These results demonstrate that ethanol and acetaldehyde synergistically disrupt tight junctions by a mechanism involving calcium, oxidative stress, Src kinase and MLCK.

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mentioning

confidence: 99%

Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers

Samak

Gangwar

Meena

et al. 2016

Sci Rep

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“…Aber auch extrahepatische Gewebe wie die gastrointestinale Mukosa, das Pankreas und das bronchopulmonale Epithel zeigen CYP2E1, und Alkohol induziert auch dieses CYP2E1. Wir fanden eine zwei-bis dreifache Erhöhung von CYP2E1 nach Alkoholzufuhr in der Mukosa des Dünn- [21,22] und Dickdarms [23] und in den Lungen [22,24,25] von Nagern. Darüber hinaus besitzen auch das Pankreas [26] und das Gehirn [27] CYP2E1.…”

Section: Induktion Im Tierexperimentsunclassified

Die Bedeutung von Cytochrom P4502E1 bei der alkoholischen Lebererkrankung und bei der alkoholmediierten Karzinogenese

Seitz

Mueller

2019

Z Gastroenterol

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ZusammenfassungVerschiedene Faktoren sind in der Pathogenese der alkoholischen Lebererkrankung (ALE) und der alkoholvermittelten Karzinogenese beteiligt. Neben genetischen, epigenetischen und immunologischen Mechanismen spielen die toxische Wirkung von Acetaldehyd, oxidativer Stress und zytokinvermittelte Entzündungen eine wesentliche Rolle. Oxidativer Stress mit der Generierung von reaktiven Sauerstoffspezies (ROS) entsteht entweder in der Entzündung (alkoholische Hepatitis) oder bei der Alkoholoxidation via Cytochrom P4502E1 (CYP2E1). CYP2E1 wird durch Alkohol induziert, oxidiert Äthanol zu Acetaldehyd und generiert dabei ROS. ROS führt unter anderem zu Proteinschädigung, Fibrogenese und DNA-Mutationen. Weiterhin resultiert die CYP2E1-Induktion in einer gesteigerten Prokarzinogenaktivierung und einem verstärkten Abbau von Retinol und Retinsäure, einem Faktor, der für eine geordnete Zelldifferenzierung und Zellproliferation verantwortlich ist. Eine Hemmung von CYP2E1 führt zu einer Verbesserung der ALE und zu einer Hemmung der chemisch induzierten Karzinogenese im Tierexperiment. Beim Menschen wird CYP2E1 bereits bei 40 Gramm Alkohol pro Tag innerhalb einer Woche induziert, jedoch gibt es signifikante interindividuelle Unterschiede. Der Mechanismus dafür ist unklar. Bei Patienten mit ALE korreliert CYP2E1 mit dem Ausmaß von hochkarzinogenen Etheno-DNA-Addukten in Leber und Ösophagus und mit der Schwere der Leberfibrose. Erste Ergebnisse zu einer Hemmung von CYP2E1 durch Chlormethiazol, einem spezifischen CYP2E1-Hemmer, bei Patienten mit ALE sind in Kürze zu erwarten.

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“…The increase in CYP2E1 has been reported not only in liver, but also in extrahepatic tissues such as the mucosal cells of the gastrointestinal tract (Seitz et al, 1978, 1982). In addition age plays a significant role in modeling the liver damage (Seitz and Stickel, 2007a).…”

Section: Induction Of Cytochrome P4502e1 In Alcoholic Liver Diseasmentioning

confidence: 99%

Alcoholic and non-alcoholic steatohepatitis

Neuman

French

et al. 2014

Experimental and Molecular Pathology

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This paper is based upon the “Charles Lieber Satellite Symposia” organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its comorbidities with chronic viral hepatitis in the presence or absence of human deficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

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Microsomal ethanol oxidation in the colonic mucosa of the rat

Cited by 25 publications

References 25 publications

Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers

Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers

Die Bedeutung von Cytochrom P4502E1 bei der alkoholischen Lebererkrankung und bei der alkoholmediierten Karzinogenese

Alcoholic and non-alcoholic steatohepatitis

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