Is Ethanol a Pro-Drug? Acetaldehyde Contribution to Brain Ethanol Effects

Quertemont, Étienne; Eriksson, C.J. Peter; Зиматкин, С. М.; Pronko, P. S.; Diana, Marco; Pisano, Milena; Rodd, Zachary A.; Bell, Richard R.; Ward, Roberta J.

doi:10.1097/01.alc.0000175015.51329.45

Cited by 24 publications

(21 citation statements)

References 58 publications

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“…The enzyme activity is localised exclusively in the microperoxisomes of aminergic neurone perikaryons and in glial cells (21). Many pieces of data support the notion that acetaldehyde is endowed with positive reinforcing properties, which play a crucial role in mediating ethanol euphoria and pave the way for alcohol craving (22). Animals pre-treated with catalase inhibitor AMT showed shorter ethanol narcosis period and lower mortality (23), less locomotor depression (24), blockade of ethanol-induced taste aversion and reduction of ethanol intake (25).…”

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confidence: 93%

Comparison of Ethanol and Acetaldehyde Toxicity in Rat Astrocytes in Primary Culture

Šarc

Lipnik‐Štangelj²

2009

Archives of Industrial Hygiene and Toxicology

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This study compared the effects of toxicity of ethanol and its fi rst metabolite acetaldehyde in rat astrocytes through cell viability and cell proliferation. The cells were treated with different concentrations of ethanol in the presence or absence of a catalase inhibitor 2-amino-1,2,4 triazole (AMT) or with different concentrations of acetaldehyde. Cell viability was assessed using the trypan blue test. Cell proliferation was assessed after 24 hours and after seven days of exposure to either ethanol or acetaldehyde. We showed that both ethanol and acetaldehyde decreased cell viability in a dose-dependent manner. In proliferation studies, after seven days of exposure to either ethanol or acetaldehyde, we observed a signifi cant dose-dependent decrease in cell number. The protein content study showed biphasic dose-response curves, after 24 hours and seven days of exposure to either ethanol or acetaldehyde. Co-incubation in the presence of AMT signifi cantly reduced the inhibitory effect of ethanol on cell proliferation. We concluded that long-term exposure of astrocytes to ethanol is more toxic than acute exposure. Acetaldehyde is a much more potent toxin than ethanol, and at least a part of ethanol toxicity is due to ethanol's fi rst metabolite acetaldehyde.

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confidence: 93%

Comparison of Ethanol and Acetaldehyde Toxicity in Rat Astrocytes in Primary Culture

Šarc

Lipnik‐Štangelj²

2009

Archives of Industrial Hygiene and Toxicology

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“…The investigations on the role of acetaldehyde and ethanol metabolism in the central effects of ethanol have been a long-standing issue of interest and controversy (McBride et al, 2002; Quertemont et al, 2005; Correa et al, 2012). Thus, although numerous lines of research have focused on the role of acetaldehyde in different aspects of ethanol effects, the role of its main metabolite in the biological basis of its effects and, in particular, of its reinforcing properties, are still not fully understood.…”

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confidence: 99%

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

Peana

Sánchez-Catalán

Hipólito

et al. 2017

Front. Behav. Neurosci.

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After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths. Accordingly, the effects of acetaldehyde, after its systemic or central administration and as obtained following ethanol metabolism, looked as they were extensively characterized. However, almost 5 years after this research appeared at its highest momentum, the investigations on this topic have been revitalized on at least three main directions: (1) the role and the behavioral significance of acetaldehyde in different phases of ethanol self-administration and in voluntary ethanol consumption; (2) the distinction, in the central effects of ethanol, between those arising from its non-metabolized fraction and those attributable to ethanol-derived acetaldehyde; and (3) the role of the acetaldehyde-dopamine condensation product, salsolinol. The present review article aims at presenting and discussing prospectively the most recent data accumulated following these three research pathways on this never-ending story in order to offer the most up-to-date synoptic critical view on such still unresolved and exciting topic.

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“…The liver maintains circulating levels of AA at levels of 20-155 μM (23, 24), and AA has been reported not to penetrate the blood-brain barrier or to penetrate very slowly (23,25). Thus, if the brain can oxidize Etoh, then intracerebral AA may mediate behavioral, neurochemical, and toxic effects of Etoh in the brain, possibly playing a role in the development of alcohol dependence (6,16,26).AA is difficult to measure in living systems. The concentrations of AA in liver, blood, and brain that occur with drinking lie in the micromolar range (23, 24), in contrast to millimolar levels of Etoh and Ac, and AA rapidly disappears after sample collection due to its volatility.…”

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confidence: 99%

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confidence: 99%

Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

Wang

Jiang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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It has been reported that chronic and acute alcohol exposure decreases cerebral glucose metabolism and increases acetate oxidation. However, it remains unknown how much ethanol the living brain can oxidize directly and whether such a process would be affected by alcohol exposure. The questions have implications for reward, oxidative damage, and long-term adaptation to drinking. One group of adult male Sprague-Dawley rats was treated with ethanol vapor and the other given room air. After 3 wk the rats received i.v. [2-13 C]ethanol and [1, 2-13 C 2 ]acetate for 2 h, and then the brain was fixed, removed, and divided into neocortex and subcortical tissues for measurement of 13 C isotopic labeling of glutamate and glutamine by magnetic resonance spectroscopy. Ethanol oxidation was seen to occur both in the cortex and the subcortex. In ethanol-naïve rats, cortical oxidation of ethanol occurred at rates of 0.017 ± 0.002 μmol/min/g in astroglia and 0.014 ± 0.003 μmol/min/g in neurons, and chronic alcohol exposure increased the astroglial ethanol oxidation to 0.028 ± 0.002 μmol/min/g (P = 0.001) with an insignificant effect on neuronal ethanol oxidation. Compared with published rates of overall oxidative metabolism in astroglia and neurons, ethanol provided 12.3 ± 1.4% of cortical astroglial oxidation in ethanol-naïve rats and 20.2 ± 1.5% in ethanol-treated rats. For cortical astroglia and neurons combined, the ethanol oxidation for naïve and treated rats was 3.2 ± 0.3% and 3.8 ± 0.2% of total oxidation, respectively. 13C labeling from subcortical oxidation of ethanol was similar to that seen in cortex but was not affected by chronic ethanol exposure.T he liver is the major organ for the oxidation of ethanol (Etoh) (1, 2), followed by the stomach and other organs. Acetate (Ac) generated from Etoh by the liver is consumed by the brain (3, 4), where it replaces a significant portion of cerebral glucose metabolism in humans and animals (5-8), either decreasing glucose consumption directly or compensating for glucose consumption decreased by some other effect. However, the brain may also oxidize Etoh (9-14), and that capacity is important with respect to several perspectives. The first step of Etoh oxidation generates acetaldehyde (AA), which is toxic, reactive, and potentially carcinogenic. AA is aversive systemically, as has been observed from the unpleasant effects of disulfuram, an inhibitor of AA dehydrogenase, but it has been shown to be rewarding in parts of the brain (12,15,16) especially in the posterior ventral tegmental area (17-19) by activating dopamine neurons (20)(21)(22). The liver maintains circulating levels of AA at levels of 20-155 μM (23, 24), and AA has been reported not to penetrate the blood-brain barrier or to penetrate very slowly (23,25). Thus, if the brain can oxidize Etoh, then intracerebral AA may mediate behavioral, neurochemical, and toxic effects of Etoh in the brain, possibly playing a role in the development of alcohol dependence (6,16,26).AA is difficult to measure in living systems. The ...

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Is Ethanol a Pro-Drug? Acetaldehyde Contribution to Brain Ethanol Effects

Cited by 24 publications

References 58 publications

Comparison of Ethanol and Acetaldehyde Toxicity in Rat Astrocytes in Primary Culture

Comparison of Ethanol and Acetaldehyde Toxicity in Rat Astrocytes in Primary Culture

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

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