Alcohol-induced redox changes in the liver of the spontaneously hypertensive rat

Wahid, S F Abdul; Khanna, J. M.; Carmichael, F. J.; Lindros, Kai O.; Rachamin, Gloria; Israel, Yedy

doi:10.1016/0006-2952(81)90309-9

Cited by 7 publications

(4 citation statements)

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“…Given both the increase in the K m for NAD ϩ and the reduction in the K i for NADH of rADH-47His vs. rADH-47Arg, the burst of acetaldehyde observed in animals injected with AdV-ADH-47His may not only stem from an increased initial velocity but also from the existence of relatively high NAD ϩ and low NADH levels at the time that ethanol starts being oxidized. These levels are reversed on ethanol oxidation, reaching a new redox steady state shown as 100 -400% increases in the lactate/pyruvate ratio during ethanol metabolism (25,26), which reflects relative increases in NADH vs. NAD ϩ . It has been postulated (27) that before achieving the new redox steady state, the initially high systemic pyruvate concentration available to the liver via the circulation allows a time-limited reoxidation of NADH by the action of lactate dehydrogenase, with regeneration of NAD ϩ .…”

Section: Discussionmentioning

confidence: 99%

“…A characteristic of liver alcohol dehydrogenases is that their turnover is limited by the rate of release of bound NADH from the enzyme after NAD ϩ and ethanol have generated acetaldehyde and NADH (23,24). Since ethanol metabolism per se increases the cytoplasmic NADH/NAD ϩ ratio, as seen by marked increases in the lactate/pyruvate ratio (25,26), the initial rate of acetaldehyde generation, at the start of ethanol metabolism, is expected to be close to the V max of ADH. In contrast, a lower rate of acetaldehyde generation is expected at later times, when a high steady state NADH/NAD ϩ ratio has been established.…”

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confidence: 99%

“…Points represent means Ϯ se of daily ethanol intake during the 1 h access to ethanol; 5 animals/group. Rats treated with AdV-rADH-47His (left panel) showed a 50% reduction in voluntary alcohol intake vs. control animals [ANOVA; F(1,25)ϭ71.3, PϽ0.001], whereas in rats treated with AdV-rADH-47Arg (right panel), the reduction was 30% [F(1,25)ϭ8.7, PϽ0.01].…”

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Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: development of an animal model

et al. 2009

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Humans who carry a point mutation in the gene coding for alcohol dehydrogenase-1B (ADH1B*2; Arg47His) are markedly protected against alcoholism. Although this mutation results in a 100-fold increase in enzyme activity, it has not been reported to cause higher levels of acetaldehyde, a metabolite of ethanol known to deter alcohol intake. Hence, the mechanism by which this mutation confers protection against alcoholism is unknown. To study this protective effect, the wild-type rat cDNA encoding rADH-47Arg was mutated to encode rADH-47His, mimicking the human mutation. The mutated cDNA was incorporated into an adenoviral vector and administered to genetically selected alcohol-preferring rats. The V(max) of rADH-47His was 6-fold higher (P<0.001) than that of the wild-type rADH-47Arg. Animals transduced with rAdh-47His showed a 90% (P<0.01) increase in liver ADH activity and a 50% reduction (P<0.001) in voluntary ethanol intake. In animals transduced with rAdh-47His, administration of ethanol (1g/kg) produced a short-lived increase of arterial blood acetaldehyde concentration to levels that were 3.5- to 5-fold greater than those in animals transduced with the wild-type rAdh-47Arg vector or with a noncoding vector. This brief increase (burst) in arterial acetaldehyde concentration after ethanol ingestion may constitute the mechanism by which humans carrying the ADH1B*2 allele are protected against alcoholism.

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Section: Discussionmentioning

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Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: development of an animal model

et al. 2009

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“…Thus, from a systems biology point of view, the alcohol burst should depend not only on the pyruvate generated in the liver itself but also on the ability of other organs to contribute pyruvate (and other NADH-oxidizing metabolites) to the liver. Indeed, upon ethanol metabolism, the lactate/pyruvate ratio of body tissues and plasma increases by 100 to 400% (10,32). Clearly, ethanol metabolism imposes a reduced state not only in the liver but also in other organs in the body by the export of the reduced substrates (e.g., lactate) from the liver to the periphery.…”

Section: Discussionmentioning

confidence: 99%

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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Effects of ethanol treatment and castration on liver alcohol dehydrogenase activity

Gillion¹,

Crow²,

Batt³

et al. 1985

Alcohol

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Alcohol-induced redox changes in the liver of the spontaneously hypertensive rat

Cited by 7 publications

References 27 publications

Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: development of an animal model

Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: development of an animal model

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

Effects of ethanol treatment and castration on liver alcohol dehydrogenase activity

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