Effect of 4-Methylpyrazole on ethanol elimination rate and hepatic redox changes in alcoholics with adequate or inadequate nutrition and in nonalcoholic controls

Salaspuro, Mikko; Lindros, Kai O.; Pikkarainen, P

doi:10.1016/0026-0495(78)90001-x

Cited by 52 publications

(15 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mode of inhibition is competitive, and thus the degree of inhibition is dependent on the dose of 4-MP (Blomstrand and Theorell, 1970;Li and Theorell, 1969;Theorell and Yonetani 1963). The 30% to 40% decrease in ethanol elimination rate observed in the present study is similar in magnitude to earlier studies that used similar doses (Jacobsen et al, 1996;Salaspuro et al, 1977Salaspuro et al, , 1978. No adverse effects were observed at the present 4-MP dose level of 10 to 15 mg/kg orally, which is in agreement with earlier findings (Jacobsen et al, 1988;Salaspuro et al 1977Salaspuro et al , 1978.…”

Section: Discussionsupporting

confidence: 95%

“…That the alcohol-induced increases in lactate in the venous blood were not radically altered during pretreatment with 4-MP in the present study is in line with earlier findings where only partial effects in these parameters were observed (Salaspuro et al, 1977(Salaspuro et al, , 1978. The result may be explained by dilution (Nuutinen et al, 1984) and extrahepatic metabolism as well as by the fact that the elimination of ethanol was only partly inhibited.…”

Section: Discussionsupporting

confidence: 92%

“…The result may be explained by dilution (Nuutinen et al, 1984) and extrahepatic metabolism as well as by the fact that the elimination of ethanol was only partly inhibited. In addition, an effect might have been observed in the ratio of lactate to pyruvate, as reported earlier (Blomstrand and Theorell, 1970;Inoue et al, 1984;Salaspuro et al. 1978).…”

Section: Discussionmentioning

confidence: 73%

See 2 more Smart Citations

Ethanol, Acetaldehyde, Acetate, and Lactate Levels After Alcohol Intake in White Men and Women: Effect of 4‐Methylpyrazole

Sarkola

Iles

Kohlenberg-Mueller

et al. 2002

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

The alcohol-induced elevation in blood acetate level is caused, in part, by ADH-mediated ethanol oxidation. Although no evidence was found for measurable acetaldehyde levels in the peripheral venous blood during alcohol intoxication, the effect of 4-MP on breath acetaldehyde in women supports the view that ADH-mediated acetaldehyde elevations reflected in the airways, but too low to be detected in the peripheral venous blood, may occur in women during alcohol intoxication in the present experimental conditions.

show abstract

Section: Discussionsupporting

confidence: 95%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 73%

See 1 more Smart Citation

Ethanol, Acetaldehyde, Acetate, and Lactate Levels After Alcohol Intake in White Men and Women: Effect of 4‐Methylpyrazole

Sarkola

Iles

Kohlenberg-Mueller

et al. 2002

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

show abstract

“…It has also been suggested that 4-MP might be used in the treatment of methanol poisoning in humans (4). 4-MP has been used in some investigations in humans according to this early suggestion (5)(6)(7). A wider use of (8) in clinical alcohol research has been hindered by the pronounced toxicity of its parent compound pyrazole (9).…”

mentioning

confidence: 99%

Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: An approach to therapy against methanol poisoning

Blomstrand

Östling-Wintzell

Löf

et al. 1979

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

View full text Add to dashboard Cite

ABSTRACT4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD+ oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 weeks. Their weight curves remained normal. Electron microscopy of liver, kidney, and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical chemical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the two compounds or the metabolites, leading to increased concentration in the blood of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys, elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of at most 10% of that of 4-methylpyrazole. Concurrent administration of methanol inhibited the elimination of 4-methylpyrazole about 25%, and 4-methylpyrazole produced a profound inhibition of the oxidation of methanol. 4-Methylpyrazole, at a level in the plasma of more than 10 ,iM, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. The present investigation indicates that 4-methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.

show abstract

“…Little is known about the effects of ethanol on SAM and SAH at very early time points; it is possible that the SAM/SAH ratio decreases transiently as an early response to ethanol exposure, coincident with an early shift in the NADH/NAD + ratio [7]. The shift in the NADH/NAD + ratio tends to be less pronounced in chronic ethanol exposure models than in acute models [25,26] as a result of increased re-oxidation of NADH and/or increased metabolism of ethanol through enzymes other than alcohol dehydrogenase [27]. While acute ethanol exposure can produce more dramatic changes in the NADH/NAD + ratio, changes similar to those described here have been observed in chronic ethanol models.…”

Section: Discussionmentioning

confidence: 99%

Ethanol exposure modulates hepatic S-adenosylmethionine and S-adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD+ system

Watson

Song

Kirpich

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Methionine metabolism is disrupted in patients with alcoholic liver disease, resulting in altered hepatic concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and other metabolites. The present study tested the hypothesis that reductive stress mediates the effects of ethanol on liver methionine metabolism. Isolated rat livers were perfused with ethanol or propanol to induce a reductive stress by increasing the NADH/NAD+ ratio, and the concentrations of SAM and SAH in the liver tissue were determined by high-performance liquid chromatography. The increase in the NADH/NAD+ ratio induced by ethanol or propanol was associated with a marked decrease in SAM and an increase in SAH liver content. 4-Methylpyrazole, an inhibitor the NAD+-dependent enzyme alcohol dehydrogenase, blocked the increase in the NADH/NAD+ ratio and prevented the alterations in SAM and SAH. Similarly, co-infusion of pyruvate, which is metabolized by the NADH-dependent enzyme lactate dehydrogenase, restored the NADH/NAD+ ratio and normalized SAM and SAH levels. The data establish an initial link between the effects of ethanol on the NADH/NAD+ redox couple and the effects of ethanol on methionine metabolism in the liver.

show abstract

Effect of 4-Methylpyrazole on ethanol elimination rate and hepatic redox changes in alcoholics with adequate or inadequate nutrition and in nonalcoholic controls

Cited by 52 publications

References 36 publications

Ethanol, Acetaldehyde, Acetate, and Lactate Levels After Alcohol Intake in White Men and Women: Effect of 4‐Methylpyrazole

Ethanol, Acetaldehyde, Acetate, and Lactate Levels After Alcohol Intake in White Men and Women: Effect of 4‐Methylpyrazole

Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: An approach to therapy against methanol poisoning

Ethanol exposure modulates hepatic S-adenosylmethionine and S-adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD+ system

Contact Info

Product

Resources

About