In Vitro Effects of Ethanol, Acetaldehyde and Fatty Acid Ethyl Esters on Human Erythrocytes

Tyulina, O. V.; Prokopieva, V. D.; Dodd, Rory; Hawkins, J. R.; Clay, S. W.; Wilson, Dale O.; Boldyrev, A. A.; Johnson, Peter

doi:10.1093/alcalc/37.2.179

Cited by 25 publications

(14 citation statements)

References 39 publications

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“…Further investigation is necessary to determine if the observed FAEE changes in RBCs are related to the RBC membrane disorders associated with chronic ethanol ingestion. Recently in an in vitro study, Tyulina et al showed that FAEEs cause elevated RBC hemolysis and significant elevations in phosphatidylserine externalization to the outer leaflet of the membrane bilayer (41). In this study, the observed changes were not due to ethanol or acetaldehyde, a product of oxidative ethanol metabolism.…”

Section: Resultssupporting

confidence: 50%

“…In this study, the observed changes were not due to ethanol or acetaldehyde, a product of oxidative ethanol metabolism. They also revealed that the effects of FAEE on RBC instability and structure were more pronounced when albumin was absent (41). This finding may explain why altered RBC morphology occurs with alcoholic liver disease, given that injured livers often synthesize decreased amounts of albumin.…”

Section: Resultsmentioning

confidence: 87%

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Red blood cell fatty acid ethyl esters: a significant component of fatty acid ethyl esters in the blood

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Cluette‐Brown

Teruya

et al. 2003

Journal of Lipid Research

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An association between alcoholism and abnormal red blood cell (RBC) size and shape has long been recognized (1). However, the underlying pathophysiologic mechanisms responsible for the morphologic alterations are incompletely understood (2-6). Fatty acid ethyl esters (FAEEs), esterification products of ethanol and fatty acids, have been shown to be incorporated into phospholipid bilayers up to 30 mol % of total membrane fatty acids (7). FAEEs have been implicated as mediators of ethanolinduced organ damage (8-13) and have clinical utility as markers for ethanol intake (14, 15). Serum and plasma FAEE levels closely correlate with blood ethanol levels, but these circulating FAEEs in blood persist for at least 24 h after ethanol ingestion, long after ethanol is no longer detectable (15, 16).Although the largest reservoir of FAEE synthetic capability appears to reside in the pancreas and the liver (17, 18), enzyme activity that catalyzes FAEE synthesis has been detected in RBCs, white blood cells (WBCs), and platelets. Given the much higher concentration of RBCs in the blood, it has been suggested that RBCs may provide a significant portion of the total FAEE synthase activity in whole blood (19). With this information, the possibility that RBC membranes might synthesize and sequester FAEEs in the blood has been raised.We conducted a controlled clinical trial to determine if FAEEs accumulate and persist within RBCs following ethanol ingestion. The objectives of this study were to determine: 1 ) whether FAEEs appear in RBCs following ethanol ingestion and whether RBC-associated FAEEs correlate with blood ethanol concentration; 2 ) how long FAEEs persist in RBCs after ethanol intake is discontinued; 3 ) whether the fatty acid composition of RBC FAEEs is distinct from the fatty acid composition of FAEEs in plasma; and 4 ) whether RBC and plasma FAEE species undergo a remodeling process with changes in fatty acid composition following discontinuation of ethanol ingestion. METHODSThe study was approved by the institutional review board of the Massachusetts General Hospital. A written informed consent was obtained from each volunteer prior to subject enrollment.Abbreviations: AIC, akaike information criteria; E16:0, ethyl palmitate; E18:0, ethyl stearate; E18:1, ethyl oleate; E18:2, ethyl linoleate; FAEE, fatty acid ethyl ester; GC-MS, gas liquid chromatography-mass spectrometry; RBC, red blood cell; SPE, solid-phase extraction; WBC, white blood cell.

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Section: Resultssupporting

confidence: 50%

Section: Resultsmentioning

confidence: 87%

Red blood cell fatty acid ethyl esters: a significant component of fatty acid ethyl esters in the blood

Best

Cluette‐Brown

Teruya

et al. 2003

Journal of Lipid Research

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“…Optical density was monitored at 630 nm every 0.25 s after the initiation of hypoosmotic stress to assess hemolysis. A detailed description of this method may be found elsewhere (48). Cellular fragility was determined by monitoring shear stress-induced hemolysis.…”

Section: Methodsmentioning

confidence: 99%

Functional NMDA receptors in rat erythrocytes

Makhro

Wang

Vogel

et al. 2010

American Journal of Physiology-Cell Physiology

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N-methyl-d-aspartate (NMDA) receptors are ligand-gated nonselective cation channels mediating fast neuronal transmission and long-term potentiation in the central nervous system. These channels have a 10-fold higher permeability for Ca(2+) compared with Na(+) or K(+) and binding of the agonists (glutamate, homocysteine, homocysteic acid, NMDA) triggers Ca(2+) uptake. The present study demonstrates the presence of NMDA receptors in rat erythrocytes. The receptors are most abundant in both erythroid precursor cells and immature red blood cells, reticulocytes. Treatment of erythrocytes with NMDA receptor agonists leads to a rapid increase in intracellular Ca(2+) resulting in a transient shrinkage via Gardos channel activation. Additionally, the exposure of erythrocytes to NMDA receptor agonists causes activation of the nitric oxide (NO) synthase facilitating either NO production in l-arginine-containing medium or superoxide anion (O(2)(.-)) generation in the absence of l-arginine. Conversely, treatment with an NMDA receptor antagonist MK-80, or the removal of Ca(2+) from the incubation medium causes suppression of Ca(2+) accumulation and prevents attendant changes in cell volume and NO/O(2)(.-) production. These results suggest that the NMDA receptor activity in circulating erythrocytes is regulated by the plasma concentrations of homocysteine and homocysteic acid. Moreover, receptor hyperactivation may contribute to an increased incidence of thrombosis during hyperhomocysteinemia.

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“…Although FAEEs have been shown to induce ROS generation in hepatocytes [44] and blood cells [45], no such data were available with respect to intestinal cells. In this study, exposure to EO and EP dose-dependently increased ROS generation in Caco-2 spheroids.…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Ethyl Esters Induce Intestinal Epithelial Barrier Dysfunction via a Reactive Oxygen Species-Dependent Mechanism in a Three-Dimensional Cell Culture Model

et al. 2013

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Background & AimsEvidence is accumulating that ethanol and its oxidative metabolite, acetaldehyde, can disrupt intestinal epithelial integrity, an important factor contributing to ethanol-induced liver injury. However, ethanol can also be metabolized non-oxidatively generating phosphatidylethanol and fatty acid ethyl esters (FAEEs). This study aims to investigate the effects of FAEEs on barrier function, and to explore the role of oxidative stress as possible mechanism.MethodsEpithelial permeability was assessed by paracellular flux of fluorescein isothiocyanate-conjugated dextran using live cell imaging. Cell integrity was evaluated by lactate dehydrogenase release. Localization and protein levels of ZO-1 and occludin were analyzed by immunofluorescence and cell-based ELISA, respectively. Intracellular oxidative stress and cellular ATP levels were measured by dichlorofluorescein and luciferase driven bioluminescence, respectively.ResultsIn vitro, ethyl oleate and ethyl palmitate dose dependently increased permeability associated with disruption and decreased ZO-1 and occludin protein levels, respectively, and increased intracellular oxidative stress without compromising cell viability. These effects could partially be attenuated by pretreatment with the antioxidant, resveratrol, pointing to the role of oxidative stress in the FAEEs-induced intestinal barrier dysfunction.ConclusionsThese findings show that FAEEs can induce intestinal barrier dysfunction by disrupting the tight junctions, most likely via reactive oxygen species-dependent mechanism.

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In Vitro Effects of Ethanol, Acetaldehyde and Fatty Acid Ethyl Esters on Human Erythrocytes

Cited by 25 publications

References 39 publications

Red blood cell fatty acid ethyl esters: a significant component of fatty acid ethyl esters in the blood

Red blood cell fatty acid ethyl esters: a significant component of fatty acid ethyl esters in the blood

Functional NMDA receptors in rat erythrocytes

Fatty Acid Ethyl Esters Induce Intestinal Epithelial Barrier Dysfunction via a Reactive Oxygen Species-Dependent Mechanism in a Three-Dimensional Cell Culture Model

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