Elsevier

Metabolism

Volume 56, Issue 7, July 2007, Pages 895-898
Metabolism

Acceleration of ethanol and acetaldehyde oxidation by d-glycerate in rats

https://doi.org/10.1016/j.metabol.2007.01.019Get rights and content

Abstract

The aim of the present study was to investigate whether d-glycerate (glycerate) could accelerate ethanol and acetaldehyde (AcH) oxidation in vivo in rats by circumventing the rate-limiting step, that is, the reoxidation of the reduced form of nicotinamide adenine dinucleotide. Male rats belonging to the ANA (Alko, nonalcohol) and AA (Alko, alcohol) rat lines were challenged with 1.2 g ethanol per kilogram with or without glycerate administration (0.1-1.0 g/kg). Blood ethanol, blood AcH, and liver free glycerol concentrations were determined during ethanol intoxication. Glycerate treatment, regardless of the dose, accelerated ethanol elimination by approximately 25% (P < .001) in the ANA animals. Glycerate also accelerated the AcH oxidation, but perhaps not as much as the ethanol oxidation, as indicated by a trend toward elevated AcH levels. In the experiments with the AA rats, glycerate treatment elevated hepatic free glycerol levels by about 50% (P < .05) during alcohol intoxication. The acceleration of ethanol and AcH oxidation in conjunction with elevated glycerol levels by the treatment with glycerate supports the hypothesis that the aldehyde dehydrogenase–mediated AcH oxidation can be coupled with the reduction of glycerate to d-glyceraldehyde catalyzed by the same enzyme. Such a coupling should increase the availability of the oxidized form of nicotinamide adenine dinucleotide and thus accelerate both ethanol and AcH oxidation. Further studies are needed to investigate how the AcH could be even more efficiently oxidized to reduce the harmful effects of ethanol-derived AcH.

Introduction

In a recent review it was concluded that acetaldehyde (AcH) plays a role in many of the harmful effects of ethanol [1]. Thus, it is only natural that research should be focused on how to minimize the toxic effects of this metabolite of alcohol. This could be achieved, for example, by reducing the rate of AcH formation (ie, ethanol oxidation), by increasing the rate of AcH oxidation, or by binding the AcH before it exerts its toxic effects.

Reducing the oxidation rate of alcohols by pyrazole and its derivatives has proved effective in some acute toxic conditions related to highly elevated aldehyde levels [2], [3], [4], but has not rendered general use because of the toxicity of these compounds [5].

AcH trapping in vivo has been tried in a number of ways. Compounds including penicillamine, cysteine, and methionine (precursor of cysteine) have been tested with limited success [6], [7], [8]. In humans, some success has been demonstrated by trapping the AcH in saliva by a slow-release buccal tablet of cysteine [9].

Theoretically, AcH oxidation by aldehyde dehydrogenase (ALDH) could be increased and, subsequently, AcH levels lowered by activation of the reoxidation of the reduced form of nicotinamide adenine dinucleotide (NADH) to the oxidized form (NAD+) at this reaction site. This could be achieved by a substrate that would use the same ALDH, catalyzing its reduction directly by using the ALDH-NADH complex formed in the oxidation of AcH to acetate. Such an oxidation/reduction coupling, using the ethanol oxidation to AcH by alcohol dehydrogenase (ADH) and the reversal with propionaldehyde reduced to propanol, has been demonstrated in vitro [10].

d-Glycerate (glycerate), being a product of fructose breakdown, could be the compound capable of coupling the ALDH-catalyzed oxidation with a simultaneous reduction. Such an activated NADH reoxidation could preferentially support the activation of the AcH oxidation and, thus, lower the ethanol-derived AcH levels.

In normal physiology, glycerate is formed from another product of fructose breakdown, d-glyceraldehyde (glyceraldehyde), in an ALDH-mediated, NAD+-consuming reaction, creating NADH. The aim of the present study was to investigate if this reaction could be reversed by a pharmacologic dose of glycerate, thereby activating the reoxidation of NADH into NAD+, and whether such activation would increase the ethanol and AcH oxidation rates in vivo.

Section snippets

Animals

Male ANA (Alko, nonalcohol) and AA (Alko, alcohol) rats, genetically selected for low and high alcohol drinking preference [11], were used in the present study. These rats are known to display elevated (ANA) or low (AA) AcH levels during ethanol intoxication [12]. The ANA rats belonged to the F84, 85, 87 generation and were 2 to 4 months old at experiments 1 and 2. In experiment 3, the AA rats, generation F89-90, were 3 to 5 months old. The animals were given water and a standard laboratory

Results

The AcH results from experiments 1 and 2 are listed in Table 1. Compared with ethanol alone, glycerate in conjunction with ethanol elevated the blood AcH levels 107% (lower glycerate dose) and 124% (higher dose) on average 1 hour after the ethanol administration. These elevations were, however, not significant in the separate experiments. Neither was any of the AcH differences at any other time point significant. In experiment 3, although no significant group differences were found in the blood

Discussion

The ALDH-catalyzed oxidation of AcH is currently supposed to be essentially irreversible. Thus, the functional in vivo importance of a reductive pathway of ALDH-catalyzed reactions has not been suggested before. However, the present results, which display glycerate-mediated increases in ethanol and AcH oxidation and elevated glycerol levels, demonstrate that the ALDH-catalyzed AcH oxidation may be coupled to simultaneous reduction of glycerate to glyceraldehyde at conditions involving a reduced

Acknowledgment

The authors thank Ms Hilkka Salohalla and Ms Tuula Mäkelä for skilful technical assistance.

References (19)

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