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Acetaldehyde

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Dennis R. Petersen – One of the best experts on this subject based on the ideXlab platform.

  • Acetaldehyde-Related Pathology: Bridging the Trans-Disciplinary Divide: Novartis Foundation Symposium 285 – Removal of Acetaldehyde from the body.
    Novartis Foundation Symposium, 2007
    Co-Authors: Richard A. Deitrich, Dennis R. Petersen, Vasilis Vasiliou

    Abstract:

    The reduction of Acetaldehyde back to ethanol via NAD-linked alcohol dehydrogenase is an important mechanism for keeping Acetaldehyde levels low following ethanol ingestion. However, this does not remove Acetaldehyde from the body, but just delays its eventual removal. Acetaldehyde is removed from the body primarily by oxidation to acetate via a number of NAD-linked aldehyde dehydrogenase (ALDH) enzymes. There are nineteen known ALDHs in humans, but only a few of them appear to be involved in Acetaldehyde oxidation. There are many analogous enzymes in other organisms. Genetic polymorphisms of several ALDHs have been identified in humans that are responsible for several hereditary defects in the metabolism of normal endogenous substrates. The best known ALDH genetic polymorphism is in ALDH2 gene, which encodes a mitochondrial enzyme primarily responsible for the oxidation of the ethanol-derived Acetaldehyde. This common polymorphism is known to dominantly inhibit its enzymatic activity resulting in reduced ability to clear Acetaldehyde in both homozygote and heterozygote individuals. These individuals are generally protected against alcohol abuse but are susceptible to oesophageal cancer. For those enzymes that are capable of reacting with Acetaldehyde, they may do so at the expense of their normal substrates, resulting in abnormal accumulation of these substrates. Examples of this are the aldehydes of the biogenic amines, dopamine, noradrenaline, adrenaline, serotonin and long chain lipid aldehydes such as nonenal. Not all of these enzymes are capable of efficient oxidation of Acetaldehyde; however, it is possible that Acetaldehyde may function as an inhibitor of these enzymes as well. The aldehydes whose metabolism is interfered with may also serve as inhibitors of ALDHs as well. However, this aspect of aldehyde function has not been extensively studied. A number of other mechanisms for the removal of Acetaldehyde exist. For example, reaction of Acetaldehyde with protein or nucleic acids is responsible for the disappearance of a small amount of Acetaldehyde, but may be responsible for some pathological effects of Acetaldehyde. There are a few other enzymes such as aldehyde oxidase, xanthine oxidase, cytochrome P450 oxidase and glyceraldehyde-3-phosphate dehydrogenase that are capable of oxidizing Acetaldehyde. However, these enzymes account for only a small fraction of the total activity.

  • inhibition of rat hepatic mitochondrial aldehyde dehydrogenase mediated Acetaldehyde oxidation by trans 4 hydroxy 2 nonenal
    Hepatology, 1991
    Co-Authors: Dennis R. Petersen, David Y Mitchell

    Abstract:

    The hepatic oxidation of ethanol has been demonstrated to cause peroxidation of cellular membranes, resulting in the production of aldehydes that are substrates for hepatic aldehyde dehydrogenases. It was the purpose of this study to evaluate the cooxidation of the lipid peroxidation product, trans-4-hydroxy-2-nonenal, and Acetaldehyde by high-affinity mitochondrial aldehyde dehydrogenase, which is of prominent importance in the oxidation of ethanol-derived Acetaldehyde. Experiments were performed for determination of kinetic parameters for uninhibited Acetaldehyde and 4-hydroxynonenal oxidation by semipurified mitochondrial aldehyde dehydrogenase prepared from male Sprague-Dawley rat liver. The affinity of the enzyme for the substrate at low substrate concentrations and the Michaelis-Menten constant of mitochondrial aldehyde dehydrogenase for Acetaldehyde were 25 and 10 times greater, respectively, than those determined for 4-hydroxynonenal. Coincubation of Acetaldehyde with physiologically relevant concentrations of 4-hydroxynonenal (0.25 to 5.0μmol/L) with mitochondrial aldehyde dehydrogenase demonstrated that 4-hydroxynonenal is a potent competitive or mixed-type inhibitor of Acetaldehyde oxidation, with concentration of 4-hydroxynonenal required for a twofold increase in the slope of the Lineweaver-Burk plot for Acetaldehyde oxidation by ALDH of 0.48 μmol/L. The results of this study suggest that the aldehydic lipid peroxidation product, trans-4-hydroxy-2-nonenal, is a potent inhibitor of hepatic Acetaldehyde oxidation and may potentiate the hepatocellular toxicity of Acetaldehyde proposed to be an etiological factor of alcoholic liver disease. (HEPATOLOGY 1991;13:728–734.)

Daria Mochlyrosen – One of the best experts on this subject based on the ideXlab platform.

  • cardioprotection induced by a brief exposure to Acetaldehyde role of aldehyde dehydrogenase 2
    Cardiovascular Research, 2018
    Co-Authors: Cintia B Ueta, Chehong Chen, Juliane C Campos, Ruda Prestes E Albuquerque, Vanessa Morais Lima, Mariehelene Disatnik, Angelica B Sanchez, Marisa H G Medeiros, Wenjin Yang, Daria Mochlyrosen

    Abstract:

    Aims: We previously demonstrated that acute ethanol administration protects the heart from ischaemia/reperfusion (I/R) injury thorough activation of aldehyde dehydrogenase 2 (ALDH2). Here, we characterized the role of Acetaldehyde, an intermediate product from ethanol metabolism, and its metabolizing enzyme, ALDH2, in an ex vivo model of cardiac I/R injury. Methods and results: We used a combination of homozygous knock-in mice (ALDH2*2), carrying the human inactivating point mutation ALDH2 (E487K), and a direct activator of ALDH2, Alda-1, to investigate the cardiac effect of Acetaldehyde. The ALDH2*2 mice have impaired Acetaldehyde clearance, recapitulating the human phenotype. Yet, we found a similar infarct size in wild type (WT) and ALDH2*2 mice. Similar to ethanol-induced preconditioning, pre-treatment with 50 μM Acetaldehyde increased ALDH2 activity and reduced cardiac injury in hearts of WT mice without affecting cardiac Acetaldehyde levels. However, Acetaldehyde pre-treatment of hearts of ALDH2*2 mice resulted in a three-fold increase in cardiac Acetaldehyde levels and exacerbated I/R injury. Therefore, exogenous Acetaldehyde appears to have a bimodal effect in I/R, depending on the ALDH2 genotype. Further supporting an ALDH2 role in cardiac preconditioning, pharmacological ALDH2 inhibition abolished ethanol-induced cardioprotection in hearts of WT mice, whereas a selective activator, Alda-1, protected ALDH2*2 against ethanol-induced cardiotoxicity. Finally, either genetic or pharmacological inhibition of ALDH2 mitigated ischaemic preconditioning. Conclusion: Taken together, our findings suggest that low levels of Acetaldehyde are cardioprotective whereas high levels are damaging in an ex vivo model of I/R injury and that ALDH2 is a major, but not the only, regulator of cardiac Acetaldehyde levels and protection from I/R.

  • altering substrate specificity of aldehyde dehydrogenase 3a1 to enhance Acetaldehyde metabolism in vivo 585 9
    The FASEB Journal, 2014
    Co-Authors: Chehong Chen, Leslie Cruz, Daria Mochlyrosen

    Abstract:

    Acetaldehyde is a well-know cytotoxin, and carcinogen. Detoxification of Acetaldehyde, which is mainly carried out by the mitochondrial aldehyde dehydrogenase 2 (ALDH2), is crucial to human health. High levels of Acetaldehydes are present in the saliva and in circulation after ethanol ingestion and likely contribute to the high incidence of esophageal cancer in alcoholics and in carriers of a common ALDH2 mutation (ALDH2*2) found in 540 million East Asians. Acetaldehyde is also partly responsible for behavior impairment following ethanol consumption. Therefore, means to accelerate Acetaldehyde clearance will be beneficial for human health. We previously identified an activator of ALDH2 that accelerated Acetaldehyde metabolism. Here we describe the recruitment of an additional ALDH isozyme, ALDH3A1, to accelerate the clearance of Acetaldehyde by the use of a small molecule. ALDH2 is the main isozyme that metabolizes Acetaldehyde in liver. In contrast, ALDH3A1, which is present in the stomach and mucosa of …

David Y Mitchell – One of the best experts on this subject based on the ideXlab platform.

  • inhibition of rat hepatic mitochondrial aldehyde dehydrogenase mediated Acetaldehyde oxidation by trans 4 hydroxy 2 nonenal
    Hepatology, 1991
    Co-Authors: Dennis R. Petersen, David Y Mitchell

    Abstract:

    The hepatic oxidation of ethanol has been demonstrated to cause peroxidation of cellular membranes, resulting in the production of aldehydes that are substrates for hepatic aldehyde dehydrogenases. It was the purpose of this study to evaluate the cooxidation of the lipid peroxidation product, trans-4-hydroxy-2-nonenal, and Acetaldehyde by high-affinity mitochondrial aldehyde dehydrogenase, which is of prominent importance in the oxidation of ethanol-derived Acetaldehyde. Experiments were performed for determination of kinetic parameters for uninhibited Acetaldehyde and 4-hydroxynonenal oxidation by semipurified mitochondrial aldehyde dehydrogenase prepared from male Sprague-Dawley rat liver. The affinity of the enzyme for the substrate at low substrate concentrations and the Michaelis-Menten constant of mitochondrial aldehyde dehydrogenase for Acetaldehyde were 25 and 10 times greater, respectively, than those determined for 4-hydroxynonenal. Coincubation of Acetaldehyde with physiologically relevant concentrations of 4-hydroxynonenal (0.25 to 5.0μmol/L) with mitochondrial aldehyde dehydrogenase demonstrated that 4-hydroxynonenal is a potent competitive or mixed-type inhibitor of Acetaldehyde oxidation, with concentration of 4-hydroxynonenal required for a twofold increase in the slope of the Lineweaver-Burk plot for Acetaldehyde oxidation by ALDH of 0.48 μmol/L. The results of this study suggest that the aldehydic lipid peroxidation product, trans-4-hydroxy-2-nonenal, is a potent inhibitor of hepatic Acetaldehyde oxidation and may potentiate the hepatocellular toxicity of Acetaldehyde proposed to be an etiological factor of alcoholic liver disease. (HEPATOLOGY 1991;13:728–734.)