Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate

Bradford, Blair U.; Seed, Casandra B.; Handler, Jeffrey A.; Dt, Forman; Thurman, Ronald G.

doi:10.1006/abbi.1993.1269

Cited by 45 publications

(26 citation statements)

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“…The conventional view that ethanol metabolism to acetaldehyde is carried out by class I liver alcohol dehydrogenase (ADH1; Haseba and Ohno, 2010), was obtained following animal (Bradford et al, 1993a,b; Escarabajal and Aragon, 2002; Peana et al, 2008) and human (Blomstrand and Theorell, 1970; Crow and Hardman, 1989; Sarkola et al, 2002) experiments with specific inhibitors (pyrazoles) of ADH (Figure 1). In humans, ADH1 is further classified into three subcategories, ADH1A, 1B and 1C (all inhibited by 4-methylpyrazole, 4-MP), which are the main ADHs for the oxidation of ethanol (Hempel et al, 1984).…”

Section: Peripheral Generation Of Acetaldehydementioning

confidence: 99%

“…In this regard, and after decades of attempts aimed at identifying the enzyme(s) responsible for the ADH1-independent fraction of ethanol metabolism, the research has focused on the microsomal (MEOS, mostly CYP2E1; Lieber and DeCarli, 1972; Takagi et al, 1986; Teschke and Gellert, 1986) and catalase-hydrogen peroxide (H 2 O 2 ; Aragon et al, 1985; Handler and Thurman, 1988b; Aragon and Amit, 1992; Bradford et al, 1993a,b; Lieber, 2004) ethanol oxidizing systems, as the ones that may come into account especially when blood alcohol is high or when drinking is chronic (Sánchez-Catalán et al, 2008). Indeed, the induction of MEOS activity due to chronic ethanol consumption seems to explain the accelerated rate of ethanol metabolism observed in chronic drinkers (Pikkarainen and Lieber, 1980).…”

Section: Peripheral Generation Of Acetaldehydementioning

confidence: 99%

“…In particular, ethanol metabolism in the liver is mediated predominantly by catalase-H 2 O 2 in the fasted state (Handler and Thurman, 1988b) and it is interesting to observe that 4-MP inhibits also acyl-CoA synthase, an enzyme essential to initiate the process of fatty acid oxidation (Bradford et al, 1993a,b). Nonetheless, some authors observed that pre-treatment with catalase inhibitors does not significantly affect ethanol pharmacokinetics (bioavailability, elimination; Tampier and Mardones, 1987; Aragon et al, 1989), suggesting that catalase does not participate actively to hepatic ethanol metabolism.…”

Section: Peripheral Generation Of Acetaldehydementioning

confidence: 99%

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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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Section: Peripheral Generation Of Acetaldehydementioning

confidence: 99%

Section: Peripheral Generation Of Acetaldehydementioning

confidence: 99%

Section: Peripheral Generation Of Acetaldehydementioning

confidence: 99%

See 1 more Smart Citation

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

Peana

Sánchez-Catalán

Hipólito

et al. 2017

Front. Behav. Neurosci.

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“…This was originally called the non-ADH1 pathway, and is thought to play a major role in alcohol metabolism for acute intoxication and for chronic drinkers [2–7]. Thus, the identification of the enzyme in this pathway has long been the subject of heated scientific debate, with the main candidates being the microsomal ethanol oxidizing system (MEOS) and catalase [2–12]. However, the contributions of these two enzymes to systemic alcohol metabolism have still not been clarified.…”

Section: Introductionmentioning

confidence: 99%

A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3)

Haseba

Ohno

2010

IJERPH

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The conventional view is that alcohol metabolism is carried out by ADH1 (Class I) in the liver. However, it has been suggested that another pathway plays an important role in alcohol metabolism, especially when the level of blood ethanol is high or when drinking is chronic. Over the past three decades, vigorous attempts to identify the enzyme responsible for the non-ADH1 pathway have focused on the microsomal ethanol oxidizing system (MEOS) and catalase, but have failed to clarify their roles in systemic alcohol metabolism. Recently, using ADH3-null mutant mice, we demonstrated that ADH3 (Class III), which has a high Km and is a ubiquitous enzyme of ancient origin, contributes to systemic alcohol metabolism in a dose-dependent manner, thereby diminishing acute alcohol intoxication. Although the activity of ADH3 toward ethanol is usually low in vitro due to its very high Km, the catalytic efficiency (kcat/Km) is markedly enhanced when the solution hydrophobicity of the reaction medium increases. Activation of ADH3 by increasing hydrophobicity should also occur in liver cells; a cytoplasmic solution of mouse liver cells was shown to be much more hydrophobic than a buffer solution when using Nile red as a hydrophobicity probe. When various doses of ethanol are administered to mice, liver ADH3 activity is dynamically regulated through induction or kinetic activation, while ADH1 activity is markedly lower at high doses (3–5 g/kg). These data suggest that ADH3 plays a dynamic role in alcohol metabolism, either collaborating with ADH1 or compensating for the reduced role of ADH1. A complex two-ADH model that ascribes total liver ADH activity to both ADH1 and ADH3 explains the dose-dependent changes in the pharmacokinetic parameters (β, CLT, AUC) of blood ethanol very well, suggesting that alcohol metabolism in mice is primarily governed by these two ADHs. In patients with alcoholic liver disease, liver ADH3 activity increases, while ADH1 activity decreases, as alcohol intake increases. Furthermore, ADH3 is induced in damaged cells that have greater hydrophobicity, whereas ADH1 activity is lower when there is severe liver disease. These data suggest that chronic binge drinking and the resulting liver disease shifts the key enzyme in alcohol metabolism from low-Km ADH1 to high-Km ADH3, thereby reducing the rate of alcohol metabolism. The interdependent increase in the ADH3/ADH1 activity ratio and AUC may be a factor in the development of alcoholic liver disease. However, the adaptive increase in ADH3 sustains alcohol metabolism, even in patients with alcoholic liver cirrhosis, which makes it possible for them to drink themselves to death. Thus, the regulation of ADH3 activity may be important in preventing alcoholism development.

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“…Thus, the findings from these two studies suggest that those subjects who are FHP may be more likely to have elevated hydrogen peroxide levels after an acute dose of alcohol than FHN subjects and would have elevated rates of catalase dependent alcohol metabolism. While it is not possible at this time to evaluate catalase, peroxide or fatty acid levels in the present study, there is significant evidence from work in rodents to suggest that rates of metabolism are regulated by these key components and more than one pathway of metabolism (Bradford et al, 1999;Bradford et al, 1993).…”

Section: Differences In Initial Rate Of Metabolismmentioning

confidence: 93%

Rates of ethanol metabolism decrease in sons of alcoholics following a priming dose of ethanol

Bradford¹,

Karnitsching²,

L.³

et al. 2007

Alcohol

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Rapid changes in rates of ethanol metabolism in response to acute ethanol administration have been observed in animals and humans. To examine whether this phenomenon might vary by risk for alcoholism, 23 young men with a positive family history of alcoholism (FHP) were compared to 15 young men without a family history of alcoholism (FHN). Rates of ethanol metabolism were measured in all subjects first after an initial ethanol dose (0.85 g/kg) and then, several hours later, a second dose (0.3 g/kg), and the two rates were compared. The two groups of subjects were similar in their histories of ethanol consumption. FHP subjects demonstrated faster initial rates of ethanol metabolism, 148 ± 36 mg/kg/hr, compared to FHN subjects, 124 ± 18 mg/kg/hr, p=.01. However, FHN subjects increased their rate of metabolism by 10 ± 27 percent compared to a decrease of -15 ± 24 percent in FHP subjects, p =.007. Fifty-two percent of the FHP and none of the FHN subjects exhibited a decline in metabolic rate of 20% or more, p=.0008. Since a significant proportion of FHP subjects exhibited a decrease in the second rate of ethanol metabolism, these preliminary data might help to partly explain why FHP individuals differ in their sensitivity to ethanol and are more likely to develop alcohol dependence.

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Evidence That Catalase Is a Major Pathway of Ethanol Oxidation in Vivo: Dose-Response Studies in Deer Mice Using Methanol as a Selective Substrate

Cited by 45 publications

References 0 publications

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3)

Rates of ethanol metabolism decrease in sons of alcoholics following a priming dose of ethanol

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