Blood acetaldehyde concentration gradient between hepatic and antecubital venous blood in ethanol‐intoxicated alcoholics and controls*

Nuutinen, Hannu; Salaspuro, Mikko; Valle, M; Lindros, Kai O.

doi:10.1111/j.1365-2362.1984.tb01186.x

Cited by 92 publications

(36 citation statements)

References 30 publications

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“…Examination of acetaldehyde (a metabolite of ethanol and a possible mediator of liver injury) concentrations showed that ethanol metabolism resulted in levels of acetaldehyde ranging from 20 mM at 48 h to 60 mM at 96 h of incubation. These concentrations are within the range of values reported for acetaldehyde levels observed during ethanol metabolism in vivo [37,38]. These results demonstrated that ethanol metabolism by PCLS are consistent with the data showing that PCLS were able to maintain both ADH and ALDH activities during incubation.…”

Section: Discussionsupporting

confidence: 80%

An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

Klassen

Thiele

Duryee

et al. 2008

Biochemical Pharmacology

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Alcohol abuse results in liver injury, but investigations into the mechanism(s) for this injury have been hampered by the lack of appropriate in vitro culture models in which to conduct in depth and specific studies. In order to overcome these shortcomings, we have developed the use of precision-cut liver slices (PCLS) as an in vitro culture model in which to investigate how ethanol causes alcohol-induced liver injury. In these studies, it was shown that the PCLS retained excellent viability as determined by lactate dehydrogenase and adenosine triphosphate (ATP) levels over a 96-h period of incubation. More importantly, the major enzymes of ethanol detoxification; alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P4502E1, remained active and PCLS readily metabolized ethanol and produced acetaldehyde. Within 24 h and continuing up to 96 h the PCLS developed fatty livers and demonstrated an increase in the redox state. These PCLS secreted albumin, and albumin secretion was decreased by ethanol treatment. All of these impairments were reversed following the addition of 4-methylpyrazole, which is an inhibitor of ethanol metabolism. Therefore, this model system appears to mimic the ethanol-induced changes in the liver that have been previously reported in human and animal studies, and may be a useful model for the study of alcoholic liver disease.

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Section: Discussionsupporting

confidence: 80%

An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

Klassen

Thiele

Duryee

et al. 2008

Biochemical Pharmacology

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“…Intracolonic acetaldehyde can be thus absorbed to the portal vein (MatysiakBudnik et al, 1996) and give higher levels in vivo. In addition, acetaldehyde concentration in hepatic vein has been reported to be 10 to 30 times higher (0.1-67.9 M) than that in the peripheral vein (Ͻ2 M) (Nuutinen et al, 1984) and chronic alcoholics exhibit high levels (30 M) of acetaldehyde (Hatake et al, 1990) in peripheral vein. Furthermore, more prominent and remarkable elevation of blood acetaldehyde has been observed after a high than a low dose of ethanol (Nuuinen et al, 1983), suggesting a significant amount of acetaldehyde accumulation in hepatocytes after heavy alcohol consumption.…”

Section: Discussionmentioning

confidence: 99%

Temporal Activation of p42/44 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase by Acetaldehyde in Rat Hepatocytes and Its Loss after Chronic Ethanol Exposure

Lee¹,

Aroor²,

Shukla³

2002

J Pharmacol Exp Ther

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Several cell-damaging effects of ethanol are due to its major metabolite acetaldehyde but its mechanisms are not known. We have studied the effect of acetaldehyde on p42/44 mitogenactivated protein kinase (MAPK) and p46/p54 c-Jun N-terminal kinase (JNK 1/2) in rat hepatocytes. Acetaldehyde caused peak activation of p42/44 MAPK at 10 min followed by JNK activation at 1 h. These responses were acetaldehyde dose-dependent (0.2-5 mM). There was a consistently higher activation of p46 JNK than p54 JNK. Ethanol also activated both p42/44 MAPK and p46/p54 JNK. The activation of JNK by ethanol, however, was not significantly affected by treatment of hepatocytes with 4-methylpyrazole, an alcohol dehydrogenase inhibitor. Cells treated with 200 mM ethanol for 1 h accumulated 0.35 Ϯ 0.02 mM acetaldehyde, but the magnitude of JNK activation was greater than that expected with 0.35 mM acetaldehyde. Thus, ethanol-activated JNK may be both acetaldehyde-dependent and -independent. The activation of JNK by ethanol or acetaldehyde was insensitive to the treatment of hepatocytes with genistein (tyrosine kinase inhibitor) and 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide (GF109203X) (protein kinase C inhibitor). Remarkably, in contrast to the above-mentioned effects on normal hepatocytes, acetaldehyde was unable to increase JNK activity in hepatocytes isolated from rats chronically fed ethanol for 6 weeks and indicated a loss of this acetaldehyde response. Thus, temporal activation of the p42/44 MAPK and p46/p54 JNK, the greater activation of p46 JNK than p54 JNK, and loss of JNK activation after chronic ethanol exposure indicate that these kinases are differentially affected by ethanol metabolite acetaldehyde.

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“…At a blood-ethanol concentration above 1-2 mmol l-1, the ADH enzymes are saturated with substrate and the metabolism of ethanol occurs at a constant velocity resulting in steady production of acetaldehyde (Lundquist, 1983). Boosting the rate of ethanol oxidation by feeding fructose accentuates the outflow of acetaldehyde from the liver and the levels in peripheral blood also rise (Nuutinen et al, 1984). Inhibition of ADH isoenzymes with 4-methyl pyrazole causes a sudden drop in the acetaldehyde output from the liver (Lindros etal., 1981).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, a change in the activity of ALDH isoenzymes by CC treatment dramatically increases the blood-acetaldehyde level (40-200 pumol 1-1). This vastly exceeds the hepatic concentration of acetaldehyde normally encountered during ethanol metabolism which are less than 10 ,umol I( Nuutinen et al, 1983Nuutinen et al, , 1984). An abnormally high concentration of acetaldehyde might be expected to shift the equilibrium reaction back towards ethanol.…”

Section: Discussionmentioning

confidence: 99%

Concentration‐time profiles of ethanol and acetaldehyde in human volunteers treated with the alcohol‐sensitizing drug, calcium carbimide.

Jones¹,

Neiman²,

Hillbom³

1988

Brit J Clinical Pharma

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1 The disposition kinetics of ethanol and its toxic metabolite acetaldehyde were investigated in 10 healthy male volunteers who ingested 0.25 g kg-' ethanol after an overnight fast. This dose of ethanol was given 2 h after they swallowed a tablet of either calcium carbimide CC (50 mg), a potent inhibitor of low Km aldehyde dehydrogenase (ALDH), or placebo according to a single-blind crossover design. 2 The pulmonary blood concentrations of ethanol and acetaldehyde were estimated indirectly by means of a gas chromatographic method modified for analysis of end-expired breath. This non-invasive sampling technique allowed replicate determinations at 15 min intervals.3 The distribution volume of ethanol (V) was 0.64 ± 0.023 1 kg-' after CC and 0.68 ± 0.0261 kg-1 after placebo treatment (P > 0.05). The zero order slope of the blood-ethanol decay profile (ko) decreased by about 5% when low Km ALDH was inhibited. The elimination of ethanol from the body (V x ko) was 1.9 ± 0.051 mmol kg-' h-1 after CC compared with 2.11 ± 0.056 mmol kg-' h-1 in placebo control experiments (P < 0.001). The area under the ethanol concentration time curve (0 -* 180 min) increased after CC treatment implying a change in clearance. 4 The disposition of acetaldehyde was markedly different in subjects pretreated with CC. The peak blood-concentrations, estimated by analysis of breath, ranged from pxmol I-1 compared with 1.7-6.5 ,umol F-1 after placebo. The apparent elimination half-life of acetaldehyde after inhibition of ALDH was 23 min on average with a range of 18-31 min. The area under the acetaldehyde-time curve (0 -> 180 min) was increased significantly after CC pretreatment. 5 The calcium carbimide-ethanol interaction caused intense facial flushing in all subjects tested beginning 20-30 min after drinking. Despite abnormally high concentrations of acetaldehyde in blood and breath after pretreatment with CC, the elimination kinetics of ethanol were not markedly changed from the placebo control trial. Our results do not support a significant role of acetaldehyde in regulating in vivo oxidation of ethanol in humans.Keywords ethanol acetaldehyde ALDH metabolism calcium carbimide kinetics breath analysis flush reaction

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Blood acetaldehyde concentration gradient between hepatic and antecubital venous blood in ethanol‐intoxicated alcoholics and controls*

Cited by 92 publications

References 30 publications

An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

Temporal Activation of p42/44 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase by Acetaldehyde in Rat Hepatocytes and Its Loss after Chronic Ethanol Exposure

Concentration‐time profiles of ethanol and acetaldehyde in human volunteers treated with the alcohol‐sensitizing drug, calcium carbimide.

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