Acetaldehyde accumulation

Some people exhibit facial flushing after consuming only modest amounts of ethanol, due to acetaldehyde accumulation. 

The answer is D. Many Asians lack a low-AJjj form of acetaldehyde dehydrogenase, which is responsible for detoxifying acetaldehyde generated by oxidation of ethanol in the liver. Acetaldehyde accumulation in the blood of such individuals leads to the facial flushing and neurologic effects exhibited by the man of Japanese descent. 

Measurements of acetaldehyde accumulation were reported in some of the earliest descriptions of the MOX process, where 5 months of MOX at 3 mL/L/month was found to raise the acetaldehyde concentration to 33 mg/L, compared to a control wine at 13 mg/L (Moutounet et ah, 1996). Further trials at Oenodev for a Syrah wine in 300-L tanks, and subject to elevated O2 delivery rates of 30,60, or 90 mL/L/month for 3 weeks, have shown that acetaldehyde will progressively accumulate to be perceived by a tasting panel from an early stage. Increased concentrations of acetaldehyde by GC were cordirmed for all treatments over the control by the end of the trial, with very high concentrations (50 mg/L) seen in the 90-mL/L/month MOX treatment (Oenodev, 2009). 

Oxidation of acetaldehyde is inhibited by disulfiram, a drug that has been used to deter drinking by alcohol-dependent patients undergoing treatment. When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. Several other drugs (eg, metronidazole, cefotetan, trimethoprim) inhibit ALDH and can cause a disulfiram-like reaction if combined with ethanol. 

There are also genetic factors that are protective against alcoholism. Approximately half of Asian populations have a gene that interferes with the metabolism of alcohol, and a toxic metabolite of alcohol accumulates in their body. When they drink alcohol, acetaldehyde accumulates, and they experience the very unpleasant symptoms of rapid heartbeat, flushing, heat, and dropping blood pressure, and they feel intoxicated with very low levels of alcohol in their blood. These individuals rarely, if ever, abuse alcohol. All the genetic factors combined explain about 60% of the risk of alcoholism, with environmental factors contributing about 40% (Schuckit, 2003). 

Fig. 2. Pathway of ethanol utilization and ethyl acetate or acetaldehyde production by Candida utilis TCA cycle activity inhibited under ircn-limited conditions. Acetyl-CoA synthetase forward inhibited by acetaldehyde accumulated when elevated levels cf ethanol ( 3.5J w/v) present in the medium.

Disulfiram has multiple mechanisms of toxicity. Its most well-defined action is inhibition of aldehyde dehydrogenase, which thereby diminishes the breakdown of acetaldehyde. Accumulation of carbon disulfide, a disulfiram metabolite, as well as inhibition of dopamine-/f-hydroxylase has also been associated with its toxicity. 

Maturation effected the following changes In enzymes and metabolites in orange fruit ethanol and acetaldehyde accumulated to levels of 10 mM and 0.08 mM, pyruvate decreased about 30%, pyruvate decarboxylase increased over 4 fold, alcohol dehydrogenase increased about 2 fold, the NADH to NAD ratio increased 21/2 fold and the terminal oxidase developed CN-insensitivity. The fraction of the total alternative respiratory pathway in actual use increased from 0.46 to 1.08. Induction of the alternative, CN-insensitive oxidase during maturation was interpreted as indicating that membrane function was modified which affected metabolic pathways resulting in the accumulation of ethanol and acetaldehyde. 

Many of the toxic effects of chronic ethanol consumption result from accumulation of acetaldehyde, which is produced from ethanol both by alcohol dehydrogenases and MEOS. Acetaldehyde accumulates in the liver and is released into the blood after heavy doses of ethanol (Fig. 25.7). It is highly reactive and binds covalently to amino groups, sulfhydryl groups, nucleotides, and phospholipids to form addncts. ... 

In that It markedly Inhibits hepatic alcohol dehydrogenase l. This action of butyraldoxlme Is not unexpected in view of the earlier observation that hydroa lanlne and pyruvoxlne Inhibit alc< ol dehydrogenase in vitro, Witii a short interval between administratlm of butyral-doxime and alcohol, acetaldehyde accumulation is suppressed and alcohol disappearance is ratarded, because of the concomitant inhibition of the rate-limiting alcohol dehydrogenase step. 

One ml t assume In any case that the question of whether metronidazole plus alcohol leads to acetaldehyde accumulation and the acetaldehyde syndrome could be confirmed unequivocally. But even this remains unresolved. Although several clinicians report clinical evidence of acetaldehyde accumulation, others are as emphatic In denying that It occurs. Disparate evidence on the effect of metronidazole on alccdiol levels in man also exists Rowe and Atklnson saw no effect on the rate of blood alcohol disappearance using themselves as sidijects, while Montaninl et reported decreased disappearance of blood alcohol... 

Sometimes alcoholics are treated with a drug called Antabuse (disulfiram), which prevents the oxidation of acetaldehyde to acetic acid. As a result, acetaldehyde accumulates in the blood, which causes nausea, profuse sweating, headache, dizziness, vomiting, and respiratory difficulties. Because of these unpleasant side effects, the patient is less likely to use alcohol. 

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