ALDH

Pharmacology. Disulfiram is almost completely absorbed after oral administration. Because it binds irreversibly to ALDH, renewed enzyme activity requires the synthesis of new enzyme. This feature creates the potential for the occurrence of a DER for at least 2 weeks after the last ingestion of disulfiram. Consequently, alcohol should be avoided during this period. 

Disulfiram produces a variety of adverse effects, which commonly include drowsiness, lethargy, and fatigue (Chick 1999). Other more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity, are rare. Psychiatric effects of disulfiram are also uncommon. They probably occur only at higher dosages of the drug and may result from the inhibition by disulfiram of a variety of enzymes in addition to ALDH. Included among the enzymes inhibited by disulfiram is dopamine P-hydroxylase, inhibition of which increases dopamine levels, which in turn can exacerbate psychotic symptoms in patients with schizophrenia and occasionally may result in psychotic or depressive symptoms in patients without schizophrenia. 

Figure 5 Model of phosphorus (P) deficiency-induced physiological changes associated with the release of P-mobilizing root exudates in cluster roots of white lupin. Solid lines indicate stimulation and dotted lines inhibition of biochemical reaction sequences or mclaholic pathways in response to P deliciency. For a detailed description see Sec. 4.1. Abbreviations SS = sucrose synthase FK = fructokinase PGM = phosphoglueomutase PEP = phosphoenol pyruvate PE PC = PEP-carboxylase MDH = malate dehydrogenase ME = malic enzyme CS = citrate synthase PDC = pyruvate decarboxylase ALDH — alcohol dehydrogenase E-4-P = erythrosc-4-phosphate DAMP = dihydraxyaceConephos-phate APase = acid phosphatase.

Both ADH and ALDH use NAD+ as cofactor in the oxidation of ethanol to acetaldehyde. The rate of alcohol metabolism is determined not only by the amount of ADH and ALDH2 enzyme in tissue and by their functional characteristics, but also by the concentrations of the cofactors NAD+ and NADH and of ethanol and acetaldehyde in the cellular compartments (i.e., cytosol and mitochondria). Environmental influences on elimination rate can occur through changes in the redox ratio of NAD+/NADH and through changes in hepatic blood flow. The equilib-... 

Shen Y-C, Fan J-H, Edenberg HJ et al. Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism. Alcohol Clin Exp Res 1997 21 1272-1277. 

Regarding the vasculature, treatment of aortic rings with mtALDH inhibitors attenuated GTN-dependent relaxation, formation of 1,2-GDN and accumulation of cGMP. Moreover, when tolerance was induced by pre-treatment with GTN, generation of 1,2-GDN and cGMP were again decreased, as was the activity of mtALDH. In whole animals, ALDH inhibitors were shown to attenuate the hypotensive effects of GTN in rabbits and rats. 

The same group drew similar conclusions from their findings with mtALDH [99]. Cyanamide and propionaldehyde, respectively an inhibitor and a substrate of ALDH, were shown to diminish GTN-induced relaxation to the same extent in aortic tissue from tolerant and non-tolerant animals. They reasoned that inhibition of relaxation caused by cyanamide or propionaldehyde in tolerant aortae could not be via further inhibition of mtALDH and was more likely to result from non-specific inhibition of GTN-induced relaxation. 

Alcohol metabolism (Figure 6.37) occurs mainly through oxidative pathways involving the enzymes alcohol dehydrogenase (ADH), acetaldehyde dehydrogenase (ALDH),... 

Ethanal (acetaldehyde), the product of ADH and CYP action on ethanol is the substrate for isoforms of ALDH. Like ADH, ALDH isoenzymes are not entirely substrate specific and will act on aliphatic and aromatic aldehydes to generate the corresponding carboxylic acid. There are nine genes encoding ALDH isoforms and all are subject to polymorphism and the enzyme products of ALDH gene expression are found widely in... 

An estimated 50% of oriental people have the ALDH-2/2 variant and thus the inactive isoenzyme, which probably accounts for the far lower incidence of heavy drinkers found amongst Chinese and Japanese than, say, Caucasians. Disulfiram is a drug used to treat alcoholics its action is to inhibit ALDH thus creating in heavy or compulsive drinkers an unpleasant and hopefully deterrent reaction. 

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... 

However, the hemiaminal 17 is unstable as a free base and readily undergoes exchange reactions. Since the hydroxy moiety of 17 is more easily displaced than the amine moiety, a highly reactive cyclopropyliminium salt 18 is formed, which then reacts with weak nucleophiles such as ethanol, to give e. g., 19. Otherwise in water solution 17 can also probably eliminate ammonia to form the highly reactive cyclopropanone 20, which is in equilibrium with its hydrate 21 and hemi-acetal 22, Eq. (8) [20]. It has been reported that hydrate 21 is also a potent inhibitor of ALDH [20,21]. 

It has been suggested that the inhibition of ALDH by AGP 17 starts with an interaction between the amino group of 17 and the cysteinyl thiolate side chain of the enzyme to form a modified holoenzyme, or that the enzymic reaction may either proceed through the cyclopropanone 20 yielding 24 a or through the imi-nium ion 18, yielding the modified enzyme 24b [17]. Thus, the covalent he-mithioacetal 24a or hemithioaminal enzyme derivatives 24b rapidly accumulate in the enzyme microenvironment and lead to the observed activity loss, Eq. (9) [21]. 

Other enzymes may also be similarly inactivated by such cyclopropanone adducts generated in situ by catalytic unravelling of some latent precursors. NAD+ as coenzyme favours the electrophilic attack of AGP 17 on the enzymic thiol group, and considerably increases the rate of inhibition [17]. ALDH in brain was also inhibited in rats pretreated with coprine, and aldehyde reductase was slightly inhibited by AGP 17, in vitro [22]. 

Thus the cyclopropanone hydrate 21 is an inhibitor of yeast aldehyde dehydrogenase (ALDH) through the nucleophilic substitution of a hydroxyl group by an enzymic thiol 47 leading to the cyclopropanone hemithioacetal 24 a, Eq. (16) [211. 

Most of the alcohol distributes into body water, but like most solvents and anesthetics some distributes into fat. It is excreted in the urine and breath, hence the utility of taking breath samples to evaluate alcohol exposure. The majority of alcohol is metabolized in the liver. Alcohol dehydrogenase (ADH) metabolizes alcohol to acetaldehyde. Acetaldehyde is toxic, with elevated levels causing flushing, headache, nausea, and vomiting. Acetaldehyde is in turn quickly metabolized to the less toxic acetate by acetaldehyde dehydrogenase (ALDH) (Figure 3.1). 

Newer strategies for stem cell identification have been developed based on the knowledge of cell functions. A primitive and multipotential subpopulation of bone marrow mononuclear cells has been identified on the basis of the intracellular presence of aldehyde dehydrogenase (ALDH). Those cells can be marked on the basis of the presence of ALDH and are called aldehyde dehydrogenase-bright cells (ALDH cells), allowing for their separation from a bone marrow aspiration mononuclear subpopulation under fluorescence-activated cell sorter (FACS) analysis. 

Much of the acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH). The product of this reaction is acetate (Figure 23-1), which can be further metabolized to C02 and water, or used to form acetyl-CoA. 

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. 

Some people, primarily of Asian descent, have a genetic deficiency in the activity of the mitochondrial form of ALDH. 

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