Ethyl alcohol metabolism in animal tissues

Ethanol is normally metabolized at a constant rate by the liver of man and animals. Attempts to change this rate have included treatment with metabolically active substances such as glucose, pyruvate, amino acids, dinitrophenol, insulin, and thyroid hormone. In some cases an increase has been observed, but usually only a very small one. The only exception so far discovered is the effect of fructose, first demonstrated by Stuhlfauth and Neumaier (1). This was confirmed by Pletscher, Bernstein, and Staub (2), who found an average increase in the elimination rate of ethanol of 80% in dogs receiving 1 to 2 g of fructose per kg per hour, and about 70% in human subjects who had fructose infused intravenously in comparable quantities (3). Oral ingestion of fructose in man gave the same result (4). Smaller or no effects have also been reported (5, 6), but in these cases the amount of fructose given was probably -insufficient.Several explanations of the phenomenon (which we shall refer to as the "fructose effect") have been offered, but since none of them were supported by direct experimental evidence, a detailed, quantitative investigation of the problem appeared desirable. Furthermore, it was of interest to study the circulatory and metabolic reactions of the liver during accelerated ethanol metabolism, as previous studies have shown that under normal con-

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“…Apparently ethanol does not by itself cause the oxygen consumption of the liver to rise, either in vitro (31) or in vivo (7).…”

Section: Resultsmentioning

confidence: 99%

The Mechanism of the Fructose Effect on the Ethanol Metabolism of the Human Liver*

Tygstrup¹,

Winkler²,

Lundquist³

1965

J. Clin. Invest.

141

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“…I n spite of major differences in basal oxygen consumption, the rate of ethanol oxidation is not appreciably influenced by treatment with triiodothyronine or with propyl thiouracil [21,29,30]. It has been calculated that in a normal liver about 7501, of the oxygen consumption is due to the oxidation of NADH liberated in the breakdown of ethanol to acetate [31,32]. Consequently, the normal CO, production from the tricarboxylic acid cycle is inhibited and the respiratory quotient falls to very low values [6,12,20].…”

Section: Ethanol-induced Changes In the Redox Xtate Inmentioning

confidence: 99%

Interference of Ethanol and Sorbitol with Hepatic Ketone Body Metabolism in Normal, Hyper‐ and Hypothyroid Rats

Lindros

1970

European Journal of Biochemistry

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I . Rats pretreated with triiodothyronine or propylthiouracil were compared with normal rats with respect to the changes induced by ethanol or sorbitol in the levels of ketone bodies and acetyl coenzyme A and in the mitochondrial redox state of the NAD couple in the intact liver after overnight fasting.2. A single dose of ethanol (2.5 g/kg) increased the ketone body level and the acetyl-CoA content after 75 min in both normal and hyperthyroid rats but not in hypothyroid rats.3. Infusion of sorbitol (0.5 g/kg) resulted in decreases in both ketone formation and levels of acetyl-CoA after 15 min in all types of rats.4. The 8-hydroxybutyratelacetoacetate ratio, which represents the redox state of the NAD couple in the mitochondria, was increased more than three-fold by treatment with ethanol in normal rats, but only by 50 in hyperthyroid rats. A ten-fold increase in the redox state of the mitochondria was caused by ethanol in hypothyroid rats, as the result of a strongly diminished acetoacetate level.5. Sorbitol infusion resulted in slight increase of the p-hydroxybutyratelacetoacetate ratio in normal and hypothyroid rats but decreased the ratio in hyperthyroid rats.6. The different ketone body levels observed in these situations were not found to be related to changes in the mitochondrial redox state, but a highly significant correlation ( P < 0.001)was observed between the changes in the content of acetyl-CoA and the ketone bodies.Among the factors suggested to control the rate of ketone body formation in the liver, the intramitochondrial redox state of the NAD couple is currently believed to be one of central importance [I-41. This topic has recently been reviewed by Wieland [5]. The rapid oxidation of fatty acids in different situations of ketonaemia apparently accelerates the intramitochondrial production of NADH. The metabolism of both ethanol and sorbitol is initiated by NADcoupled dehydrogenases located mainly in the cytoplasm, and consequently the oxidation of both of these substrates increases the NADH/NAD+ ratio in the cytoplasm [6--111.

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“…The activity of this enzyme is very high and sufficient to account for the increase in ethanol oxidation during fructose metabolism [66], provided the production of oxaloacetate is increased in this condition. Oxaloacetate has been demonstrated to increase ethanol oxidation rate in rat liver slices [57]. As malate accumulates in the liver cell during fructose metabolism [58,59], the flow of malate through the reaction catalyzed by the malic enzyme is thought to be rate-limiting for the increase in ethanol oxidation rate.…”

Section: The Malic Enzyme Shuttlementioning

confidence: 99%

Effect of Fructose and Glyceraldehyde on Ethanol Metabolism in Human Liver and in Rat Liver

Thieden

Grunnet

Damgaard

et al. 1972

European Journal of Biochemistry

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The basic kinetic parameters, V and Km, have been determined for liver enzymes involved in the metabolism of fructose and ethanol in rats and man. Values, previously not reported, or which deviate significantly from those reported in the literature are as follows: The maximal activity of aldehyde dehydrogenase from human liver with acetaldehyde as substrate was determined as 43 pmol x min-l x g wet wt-l. The activity of NADP-dependent alcohol dehydrogenase with ethanol as substrate both in rat liver and in human liver was very low. The presence of glycerate kinase (12 pmol x min-l x g wet &-I) in human liver has been established. The K,-value of human-liver alcohol dehydrogenase (NAD) for D-glyceraldehyde was determined as 80-90mM compared to 8-10mM for the rat liver enzyme. The NADP-dependent alcohol dehydrogenase from human liver had a Km-value for D-glyceraldehyde of 2.5-3.3 mM. Glycerate kinase from human and rat liver had K,-values for D-glyceraldehyde of 2.5-3.0 mM and 0.03 mM, respectively.I n slices of human liver the increase in ethanol-oxidation rate caused by 11 mM fructose ('the fructose effect') or by 2 mM D-glyceraldehyde was 76O/, and 56O/,, respectively.I n rat-liver slices the effect of D-glyceraldehyde upon ethanol metabolism was inhibited 1000/o by rotenone. I n the same experiments rotenone caused a 5001, inhibition of the basic ethanol oxidation rate and of the oxygen consumption.10 mM pyruvate, in experiments with liver slices from fasted rats, caused a 9001, increase in the ethanol oxidation rate in the absence of CO,, but only a 200/, increase in the presence of CO,. CO, in itself caused a 700/, increase in the unstimulated oxidation of ethanol.Kinetic considerations and results reported in this paper held together with results from other laboratories lead to the conclusion that the theories previously proposed for the effect of fructose, D-glyceraldehyde or pyruvate upon ethanol metabolism are irreconcilable with the experimental results. A new hypothesis for the 'fructose effect' is proposed.Malate dehydrogenase, malic enzyme, pyruvate carboxylase and transfer of oxaloacetate from the mitochondria1 to the extramitochondrial compartment constitute a mechanism by which transfer of hydrogen from NADH to NADP may take place, thus increasing the rate of removal of NADH from the cytoplasm.I n the liver ethanol is oxidized to acetate via acetaldehyde. The oxidation to acetaldehyde, catalyzed by the cytosolic alcohol dehydrogenase, has been thought to be the rate-limiting step in ethanol metabolism [I]. There is, however, no correlation between the alcohol dehydrogenase activity measured in vitro and the rate of ethanol oxidation in vivo or in liver slices [2,3,4]. As the activity of the enzyme does not appear to be the rate-limiting factor, it is assumed that the oxidation of NADH is ratelimiting for the ethanol oxidation in vivo.During ethanol metabolism acetaldehyde does not accumulate in the liver and is probably oxidized immediately by aldehyde dehydrogenase to acetate [ 5 ] . Thus 2 mol N...

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Ethyl alcohol metabolism in animal tissues

Cited by 118 publications

References 3 publications

The Mechanism of the Fructose Effect on the Ethanol Metabolism of the Human Liver*

The Mechanism of the Fructose Effect on the Ethanol Metabolism of the Human Liver*

Interference of Ethanol and Sorbitol with Hepatic Ketone Body Metabolism in Normal, Hyper‐ and Hypothyroid Rats

Effect of Fructose and Glyceraldehyde on Ethanol Metabolism in Human Liver and in Rat Liver

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