Aldehyde dehydrogenase, effect

Disulfiram works by irreversibly blocking the enzyme aldehyde dehydrogenase, a step in the metabolism of alcohol, resulting in increased blood levels of the toxic metabolite acetaldehyde. As levels of acetaldehyde increase, the patient experiences decreased blood pressure, increased heart rate, chest pain, palpitations, dizziness, flushing, sweating, weakness, nausea and vomiting, headache, shortness of breath, blurred vision, and syncope. These effects are commonly referred to as the disulfiram-ethanol reaction. Their severity increases with the amount of alcohol that is consumed, and they may warrant emergency treatment. Disulfiram is contraindicated in patients who have cardiovascular or cerebrovascular disease, because the hypotensive effects of the disulfiram-alcohol reaction could be fatal in such patients or in combination with antihypertensive medications. Disulfiram is relatively contraindicated in patients with diabetes, hypothyroidism, epilepsy, liver disease, and kidney disease as well as impulsively suicidal patients. 

Chou W-Y, Stewart MJ, Carr LG, Zheng D, Stewart TR, Williams A, Pinaire J, Crabb DW. An A/G polymorphism in the promoter of mitochondrial aldehyde dehydrogenase (ALDH2) effects of the sequence variant on transcription factor binding and promoter strength. Alcohol Clin Exp Res 1999 26 963-968. 

Nevertheless, the nature and function of this cofactor will have to be clarified by further investigations. It is possible that this problem is involved in the way by which the energy for reduction is provided, whether NADH2 or NADPH2 is oxidized by the action of MHbR (cf. G5, R12, S10, Sll, S17). This may be implicated in the results showing the enhancement of MHb reduction by aliphatic and aromatic aldehydes effected by a NAD-linked aldehyde dehydrogenase (M9, M10). 

F. M. Dickinson, G. W. Haywood, The Effects of Mg2+ on Certain Steps in the Mechanism of the Dehydrogenase and Esterase Reactions Catalysed by Sheep Liver Aldehyde Dehydrogenase. Support for the View That Dehydrogenase and Esterase Activities Occur at the Same Site on the Enzyme , Biochem. J. 1986, 233, 877-883. 

A very high activity of mitochondrial aldehyde dehydrogenases (together with its low ensures very efficient oxidation in the liver so that the concentration of acetaldehyde in blood remains very low. Nonetheless, it is possible that some of the pathological effects of ethanol are due to acetaldehyde (ethanal). In contrast, a large proportion of the acetate escapes from the liver and is converted to acetyl-CoA by acetyl-CoA synthetase in other tissues ... 

The effect is mainly due to the inhibition of NAD+-dependent aldehyde dehydrogenase (ALDH) which causes an accumulation of acetaldehyde in the body after ethanol ingestion [17]. The compound responsible for the physiological activity of C. atramentarius is coprine 16, a AT -(l-hydroxycyclopropyl)-L-glutamic acid amide which has been isolated and synthesized, [16a,b]. Thus, when fed... 

Toxicology. Cyanamide is an irritant of the eyes, mucous membranes, and skin it is an inhibitor of aldehyde dehydrogenase and can cause an antabuse effect with ethanol ingestion. 

Most of the human experience with disulfiram has come from its use as an avoidance therapy for alcoholism. Metabolites of disulfiram inhibit aldehyde dehydrogenase, resulting in elevated levels of acetaldehyde after ethanol ingestion. Side effects include flushing of the face, tachycardia, severe headache, apprehension, hyperpnea, hypotension, dizziness, nausea, vomiting, and fainting. Severe reactions may include convulsions, myocardial infarction, and marked respiratory depression. ... 

One important mechanism of serotonin elimination is the (re-) uptake, e.g. by platelets. Furthermore, serotonin is metabolized by monoaminox-idase to 5-hydroxyindoleacetaldehyde and, subsequently, by an aldehyde dehydrogenase to 5-hydroxyindolacetic acid. The vascular effects of serotonin are complex. The direct interaction with vascular smooth muscle induces a vasoconstriction, whereas the stimulation of 5-HT-receptors on the endothelium induces the release of vasorelaxant factors with a dilatation as a result. An intravenous application of serotonin increases the pressure in the pulmonary circulation. A continuous infusion results... 

Disulfiram Inhibits aldehyde dehydrogenase, causes aldehyde accumulation during ethanol ingestion Deterrent to relapse in individuals with alcoholism Toxicity Little effect on its own but severe and potentially dangerous flushing, headache, nausea, vomiting, and hypotension when combined with ethanol... 

Another oxidation reaction, which shows variation in human populations, is the oxidation of ethanol. This has been shown to be significantly lower in Canadian Indians compared with Caucasians, and thus the Indians are more susceptible to the effects of alcoholic drinks. The rate of metabolism in vivo in Indians is 0.101 g kg-1 hr-1 compared with 0.145 g kg-1 hr-1 in Caucasians. This seems to be due to variants in alcohol dehydrogenase, although differences in aldehyde dehydrogenase may also be involved. Variants of alcohol dehydrogenase resulting in increased metabolism have also been described within Caucasian and Japanese populations. 

A similar effect is exerted by the drug disulfiram (Antabuse), which has been used to discourage drinking and whose metabolites are thought to inhibit aldehyde dehydrogenase.95... 

The nasal route of drug delivery avoids the liver first-pass effect, but the pseudo-first-pass effect owing to nasal metabolism of drugs is still a concern. Many enzymes such as carboxylesterase, aldehyde dehydrogenase, glutathione transferases, UDP-glucoronyl transferase, epoxide hydrolases, CYP-dependent monoxygenases, exo- and endopeptidases and proteases are present in the nasal mucosa.106 108,110,116 CYP enzymes are present abundantly in the olfactory epithelium.107,110... 

Ingestion of methanol, particularly during the prohibition era, resulted in significant illness and mortality. Where epidemics of methanol poisoning have been reported, one-third of the exposed population recovered with no ill effects, one-third have severe visual loss or blindness, and one-third have died. Methanol itself is not responsible for the toxic effects but is rapidly metabolized in humans by alcohol dehydrogenase to formaldehyde, which is subsequently metabolized by aldehyde dehydrogenase to form... 

In addition to its powerful synergistic action with alcohol by the inhibition of aldehyde dehydrogenase, Disulfiram exerts an equally strong synergistic toxic effect in the presence of ethylene dibromide (EDB, ref. 179) Laboratory rats exposed to 20 ppm EDB (inhalation)... 

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