The importance of alcohol dehydrogenase in regulation of ethanol metabolism in rat liver cells

Page, Rachel; Kitson, Kathryn E.; Hardman, Michael J.

doi:10.1042/bj2780659

Cited by 23 publications

(10 citation statements)

References 25 publications

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“…Whereas studies agree that in the rat, under steady-state conditions, 50 -60% of the maximal capacity of ADH is used to oxidize ethanol (2,19), in humans the maximal activity of ADH does not appear to constitute a major rate-limiting step in the metabolism of ethanol. This is seen in well-conducted studies showing that the rate of ethanol metabolism is only minimally changed or is unchanged in individuals who carry the ADH1B*2 allele (5, 18), encoding an ADH that in vitro has a maximum activity that is one order of magnitude greater than that encoded by ADH1B*1 (9).…”

Section: Discussionmentioning

confidence: 87%

Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective

Quintanilla¹,

Tampier²,

Sapag³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Individuals who carry the most active alcohol dehydrogenase (ADH) isoforms are protected against alcoholism. This work addresses the mechanism by which a high ADH activity leads to low ethanol intake in animals. Male and female ethanol drinker rats (UChB) were allowed access to 10% ethanol for 1 h. Females showed 70% higher hepatic ADH activity and displayed 60% lower voluntary ethanol intake than males. Following ethanol administration (1 g/kg ip), females generated a transient blood acetaldehyde increase ("burst") with levels that were 2.5-fold greater than in males (P Ͻ 0.02). Castration of males led to 1) an increased ADH activity (ϩ50%, P Ͻ 0.001), 2) the appearance of an acetaldehyde burst (3-to 4-fold vs. sham), and 3) a reduction of voluntary ethanol intake comparable with that of naïve females. The ADH inhibitor 4-methylpyrazole blocked the appearance of arterial acetaldehyde and increased ethanol intake. Since the release of NADH from the ADH ⅐ NADH complex constitutes the rate-limiting step of ADH (but not of ALDH2) activity, endogenous NADH oxidizing substrates present at the time of ethanol intake may contribute to the acetaldehyde burst. Sodium pyruvate given at the time of ethanol administration led to an abrupt acetaldehyde burst and a greatly reduced voluntary ethanol intake. Overall, a transient surge of arterial acetaldehyde occurs upon ethanol administration due to 1) high ADH levels and 2) available metabolites that can oxidize hepatic NADH. The acetaldehyde burst is strongly associated with a marked reduction in ethanol intake. male; female; orchidectomy; arterial; pyruvate; limited access ETHANOL IS METABOLIZED IN THE LIVER by alcohol dehydrogenase (ADH) into acetaldehyde, a metabolite that is subsequently oxidized into acetate by aldehyde dehydrogenase (ALDH2). Humans who carry a dominant negative mutation of the gene that codes for mitochondrial aldehyde dehydrogenase (33) display a marked elevation in blood acetaldehyde levels following ethanol intake, which curtails further alcohol use (15). Individuals carrying this allele (ALDH2*2) are protected by 66 to 99% against alcohol abuse and alcoholism (7,8,30,31). Although it has been suggested that acetaldehyde generated in the brain may be a rewarding metabolite (20), high levels of blood acetaldehyde are aversive, as shown by the marked inhibition of ethanol intake in animals in which peripheral ALDH2 activity is reduced and blood acetaldehyde levels are increased by antisense drugs that do not penetrate the bloodbrain barrier (6).Individuals carrying an ADH allele (ADH1B*2) that codes for an isoform that is one order of magnitude more active than that coded by the usual ADH1B*1 (9) are also protected against heavy alcohol use and alcoholism (26; see also meta-analysis, Ref. 34). The highly active ADH is found in some East Asians and Ashkenazi Jews. The steady-state rate of ethanol metabolism in individuals carrying the ADH1B*2 allele is only 8 -13% greater than that of subjects carrying ADH1B*1 (18), indicating that in humans the maxima...

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Section: Discussionmentioning

confidence: 87%

Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective

Quintanilla¹,

Tampier²,

Sapag³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Seule une ponction de sang au niveau de la veine sus-hépatique aurait permis d'observer une concentration veineuse supérieure à la concentration artérielle. À forte dose d'éthanol (3 g.kg −1 ), les concentrations en acétates présentent un plateau traduisant une saturation des mécanismes enzymatiques de production (métabolisme de l'éthanol et de l'acétaldéhyde) [37,38] et/ou d'élimina-tion (métabolisme de l'acétate). Une action inhibitrice de l'éthanol sur l'alcool-déshydrogénase soit directe, soit par l'intermédiaire de son premier métabolite, l'acétaldéhyde, a été rapportée [37,[39][40][41].…”

Section: Discussionunclassified

“…Cependant la vitesse d'élimina-tion de l'éthanol ne semble pas corrélée aux concentrations d'acétaldéhyde [42] et la consommation des cofacteurs enzymatiques ne semblent pas, non plus, limiter le métabolisme de l'éthanol [37]. Plus récemment, l'hypothèse que l'alcool déshydrogénase puis l'aldéhyde déshydrogénase puissent limiter le métabolisme de l'éthanol a été avancée [38].…”

Section: Discussionunclassified

Influence du site de prélèvement sur l’étude cinétique et métabolique de l’éthanol

et al. 2012

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Résumé -Objectif : L'analyste n'obtenant pas toujours les mêmes prélèvements sanguins, nous proposons d'étudier l'influence du site de prélèvement sanguin sur l'étude cinétique et métabolique de l'éthanol. Méthode : Sur un modèle animal, le rat mâle Sprague-Dawley âgé de 7 à 9 semaines, les cinétiques sanguines de l'éthanol, sériques de l'acétate et du lactate, artérielles et veineuses, sont déterminées respectivement par analyse de l'espace de tête en chromatographie en phase gazeuse et électrophorèse capillaire de zone. L'animal est cathétérisé soit au niveau d'une artère fémorale, soit au niveau d'une veine caudale. Résultats : Lors de la phase d'absorption, l'éthanolémie artérielle croît plus rapidement et plus intensément que l'éthanolémie veineuse ; après la phase de distribution, elles tendent à se confondre. Contemporainement, les acétates, métabolites de l'éthanol, apparaissent plus concentrés dans le compartiment artériel que veineux périphérique ; les lactates, produits indirects du métabolisme de l'éthanol, présentent une cinétique artérielle similaire à celle de l'acétate, les concentrations veineuses restant anormalement élevées pendant l'étude. Conclusion : Le sang veineux prélevé lors de cette étude n'a pas donné accès à la réalité cinétique et métabolique de l'éthanol. Ainsi, en comparaison avec le compartiment artériel, l'éthanol et l'acétate sont présents en quantité moindre dans le sang veineux, l'éthanol y apparaissant plus lentement. Le sang veineux prélevé s'est même avéré inadapté à l'étude cinétique des lactates. Cette étude confirme, si nécessaire, que les résultats et l'interprétation d'une analyse sont préconditionnés par le prélèvement lui-même, ce dernier n'étant pas toujours réalisé sous les indications d'un analyste. Mots clés :Recueil de prélèvements sanguins/méthode, éthanol/sang, éthanol/métabolisme, acétates/sang, lactates/sang Abstract -Objective: Because the analyst does not always obtain the same sampling of blood, we suggest studying the influence of the site of blood sampling on kinetic and metabolic studies of ethanol. Method: On an animal model, 7-to-9-week-old Sprague-Dawley male rats, arterial and venous blood kinetics of ethanol and serum kinetics of acetate and lactate were, respectively, determined by head-space chromatography analysis and capillary zone electrophoresis. The animal is catheterized either at the femoral artery, or at the caudal vein. Results: During the absorption phase, the arterial blood ethanol grew more quickly and more intensely than the venous; after the distribution phase, they tended to merge. At the same time, acetates, produced during ethanol metabolism, were more concentrated in the arterial compartment than the venous; lactates, indirect products of ethanol metabolism, presented an arterial kinetics similar to acetate, and venous concentrations remained abnormally high throughout the study. Conclusion: The venous blood samples taken during this study did not give access to the kinetic and metabolic reality of ethanol. So, compared with t...

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“…34 A third point of view proposes that there is not a single rate‐limiting step in ethanol metabolism, and that control is shared among several steps. 35 These controversies notwithstanding, Ronis et al recently demonstrated that a significant proportion of alcohol‐mediated liver injury occurs independently of alcohol metabolism. 36 Our results, showing that KO mice develop severe steatosis despite a significant block in hepatic ethanol metabolism, are consistent with their study.…”

Section: Discussionmentioning

confidence: 99%

UV‐curable methacrylic epoxy dispersions for cationic electrodeposition coating

Kim

Hong

2006

J of Applied Polymer Sci

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UV-curable epoxy dispersions were prepared for cationic electrodeposition coating. Sequential reactions were used to introduce methacrylate groups to the epoxyamine polymer as coupling agents to the multifunctional acrylates. The molecular weight values of the prepared epoxy-amine polymer were M n ¼ 2800 and M w ¼ 4300. The neutralized epoxy-amine polymer containing photoinitiator with or without multifunctional acrylate (pentaerythritol triacrylate, PETA) could be dispersed into a stable dispersion without any phase separation. The size of the particles in these epoxy dispersions was approximately 77.7 nm, and increased with the incorporation of PETA. The electrodeposition process was introduced to the prepared epoxy dispersions, and the electrodeposited films were cured by UV irradiation after a 10-min flash off at 808C. Studies of the kinetics using photo-DSC revealed that the crosslinked films containing PETA gave a higher conversion rate than those without PETA, resulting in better resistance to methyl ethyl ketone.

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The importance of alcohol dehydrogenase in regulation of ethanol metabolism in rat liver cells

Cited by 23 publications

References 25 publications

Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective

Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective

Influence du site de prélèvement sur l’étude cinétique et métabolique de l’éthanol

UV‐curable methacrylic epoxy dispersions for cationic electrodeposition coating

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