Metabolism Of Biogenic Aldehydes Research Articles

Reduced aldehyde dehydrogenase levels in the brain of patients with Down syndrome.

Aldehyde dehydrogenase (ALDH) is a key enzyme in fructose, acetaldehyde and oxalate metabolism and represents a major detoxification system for reactive carbonyls and aldehydes. In the brain, ALDH exerts a major function in the metabolism of biogenic aldehydes, norepinephrine, dopamine and diamines and gamma-aminobutyric acid. Subtractive hybridization studies in Down Syndrome (DS) fetal brain showed that mRNA for ALDH are downregulated. Here we studied the protein levels in the brain of adult patients. The proteins from five brain regions of 9 aged patients with DS and 9 controls were analyzed by two-dimensional (2-D) gel electrophoresis and identified by matrix-assisted laser desorption ionization mass spectrometry. ALDH levels were reduced in the brain regions of at least half of the patients with Down Syndrome, as compared to controls. The decreased ALDH levels in the DS brain may result in accumulation of aldehydes which can lead to the formation of plaques and tangles reflecting abnormally cross-linked, insoluble and modified proteins, found in aged DS brain. Furthermore, we constructed a 2-Dmap including approximately 120 identified human brain proteins.

Regional distribution of low-Km mitochondrial aldehyde dehydrogenase in the rat central nervous system.

To clarify the regional capacity of the brain to oxidize biogenic aldehydes and ethanol-derived acetaldehyde, a quantitative immunohistochemical study of the microregional and cellular expression of low Km mitochondrial aldehyde dehydrogenase (mALDH; EC 1.2.1.3) in the rat central nervous system was undertaken, using antiserum raised in rabbit against low-Km aldehyde dehydrogenase purified from rat liver mitochondria. mALDH-specific immunoreactivity (IR) was observed to various extent in the majority of structures in all brain and spinal cord areas. Staining was strong in the extranuclear cytoplasm of neuronal and glial cell bodies but less pronounced in their processes and terminals, the conducting tracts, white matter and neuropile and in blood vessels. Immunostaining density was 2 to 3 times higher in neuronal perikarya as compared with neuropile. mALDH-positive neurons were found in all brain regions, being strongest in the inferior olive and hippocampus stratum pyramidale and weakest in substantia nigra. The percentage of morphologically identifiable ALDH-positive neurons ranged from 40% in the arcuate hypothalamic nucleus to 88% in the cerebellar Purkinje cells. A comparison of the heterogeneous expression of mALDH in various rat CNS regions and cells, as observed in the present study, with the corresponding previously published distributions of the potential acetaldehyde-producing enzymes ADH and cytochrome P450 2E1 indicates major differences, which may help in understanding potential acetaldehyde-mediated CNS effects of ethanol. Knowledge of the regional distribution of high-affinity aldehyde dehydrogenase should also throw light on the neurophysiological role of local regulation of the metabolism of biogenic aldehydes in the brain.

Effects of ethanol, acetaldehyde and disulfiram on the metabolism of biogenic aldehydes in isolated human blood cells and platelets

The effects of ethanol, acetaldehyde and disulfiram on the metabolism of biogenic aldehydes were measured in different human blood fractions. Intact erythrocytes, leukocytes and platelets were incubated in phosphate-buffered saline with 3,4-dihydroxyphenylacetaldehyde (DOPAL) or 5-hydroxyindole-3-acetaldehyde (5-HIAL), the aldehydes derived from dopamine and serotonin, respectively. The disappearance of the aldehyde and the formation of acid and alcohol metabolites were analysed in the presence of different concentrations of ethanol, acetaldehyde or disulfiram using high-performance liquid chromatography with electrochemical detection. Ethanol at a concentration of 20 mM did not affect the biogenic aldehyde metabolism. High concentrations of acetaldehyde caused a dose-dependent inhibition of the disappearance rate of the biogenic aldehydes and of the formation rate of acid metabolites. In incubations with leukocytes or platelets, the inhibition of the acid formation was associated with a slight increase in the formation of the alcohol metabolites. Disulfiram at a concentration of 50 μM totally inhibited the metabolism of DOPAL and 5-HIAL in incubations with erythrocytes or platelets, whereas much less inhibition was observed in incubations with leukocytes.

Metabolism of biogenic aldehydes in isolated human blood cells, platelets and in plasma

The metabolism of biogenic aldehydes was measured in different human blood fractions. Isolated erythrocytes, leukocytes, platelets and plasma were incubated with 3,4-dihydroxyphenyl-acetaldehyde (DOPAL) or 5-hydroxyindole-3-acetaldehyde (5-HIAL), the aldehydes derived from dopamine and 5-hydroxytryptamine, respectively. The disappearance of the aldehydes and the formation of acid and alcohol metabolites were analysed using high-performance liquid chromatography with electrochemical detection. The aldehydes were unstable in phosphate-buffered saline, but this non-enzymatic oxidation was prevented in the presence of EDTA, pyrophosphate or blood tissue. When DOPAL or 5-HIAL were incubated with erythrocytes, only acid metabolites were formed, whereas both acid and alcohol metabolites were formed in incubations with leukocytes or platelets. The amount of the acid metabolite exceeded that of the alcohol metabolite, both with leukocytes and platelets. No metabolites were formed when the aldehydes were incubated in plasma. The oxidation of the aldehydes in incubations with erythrocytes or platelets was totally inhibited in the presence of 50 μM of the aldehyde dehydrogenase inhibitor disulfiram. However, disulfiram did not inhibit the metabolism of DOPAL and 5-HIAL in incubations with leukocytes, suggesting that different isozymes of aldehyde dehydrogenase are present in leukocytes as compared to erythrocytes and platelets.

Identification of pig brain aldehyde reductases with the high-Km aldehyde reductase, the low-Km aldehyde reductase and aldose reductase, carbonyl reductase, and succinic semialdehyde reductase.

Four NADPH-dependent aldehyde reductases (ALRs) isolated from pig brain have been characterized with respect to substrate specificity, inhibition by drugs, and immunological criteria. The major enzyme, ALR1, is identical in these respects with the high-Km aldehyde reductase, glucuronate reductase, and tissue-specific, e.g., pig kidney aldehyde reductase. A second enzyme, ALR2, is identical with the low-Km aldehyde reductase and aldose reductase. The third enzyme, ALR3, is carbonyl reductase and has several features in common with prostaglandin-9-ketoreductase and xenobiotic ketoreductase. The fourth enzyme, unlike the other three which are monomeric, is a dimeric succinic semialdehyde reductase. All four of these enzymes are capable of reducing aldehydes derived from the biogenic amines. However, from a consideration of their substrate specificities and the relevant Km and Vmax values, it is likely that it is ALR2 which plays a primary role in biogenic aldehyde metabolism. Both ALR1 and ALR2 may be involved in the reduction of isocorticosteroids. Despite its capacity to reduce ketones, ALR3 is primarily an aldehyde reductase, but clues as to its physiological role in brain cannot be discerned from its substrate specificity. The capacity of succinic semialdehyde reductase to reduce succinic semialdehyde better than any other substrate shows that this reductase is aptly named and suggests that its primary role is the maintenance in brain of physiological levels of gamma-hydroxybutyrate.

Effects of aldehyde dehydrogenase inhibitors on enzymes involved in the metabolism of biogenic aldehydes in rat liver and brain

The effects of the aldehyde dehydrogenase inhibitors disulfiram, coprine and cyanamide on enzymes involved in the metabolism of biogenic aldehydes in rat liver and brain were studied. Both liver and brain aldehyde dehydrogenase activities were significantly decreased in rats pretreated with these drugs. In the liver, the low- K m aldehyde dehydrogenase activity was markedly decreased by all three drugs after 2 and 24 hr whereas only cyanamide inhibited the high- K m enzymes. The brain ALDH-activity with a low acetaldehyde concentration was significantly decreased by coprine and cyanamide at both times tested, whereas disulfiram caused no change after 2 hr but an inhibition of 38% after 24 hr. The brain ALDH-activity with a high acetaldehyde concentration was significantly decreased by coprine and cyanamide but not by disulfiram. The activity of the substrate specific enzyme succinate semialdehyde dehydrogenase in brain was slightly but significantly decreased in rats pretreated with cyanamide but not in rats pretreated with disulfiram or coprine. None of the drugs caused any changes in the activities of aldehyde reductase and monoamine oxidase in brains in vivo. The activity of monoamine oxidase in liver was significantly decreased by coprine after 24 hr. In contrast to the effects obtained in vivo, disulfiram was found to be an inhibitor in vitro of brain succinate semialdehyde dehydrogenase and liver monoamine oxidase. Aldehyde reductase was slightly inhibited by both disulfiram and 1-aminocyclopropanol in vitro.

Biogenic aldehyde metabolism in rat brain: subcellular distribution of aldose reductase and valproate-sensitive aldehyde reductase.

Reductase activity towards two aldose substrates has been examined in subcellular fractions prepared from rat brain. The reduction of glucuronate, which is sensitive to inhibition by the anticonvulsant drug sodium valproate, corresponds to the major high-Km aldehyde reductase in brain. Xylose reduction that is insensitive to valproate inhibition has characteristics consistent with the activity of aldose reductase (EC 1.1.1.21). Both enzymes are predominantly localized in the cytosolic fraction. The significance of the location of these two reductases is discussed in relation to the compartmentation of catecholamine metabolism in brain.

Biogenic aldehyde metabolism in rat brain: Differential sensitivity of aldehyde reductase isoenzymes to sodium valproate

The effects of inhibitors of aldehyde reductase (alcohol:NADP+ oxido-reductase, EC 1.1.1.2) on the formation of 3-methoxy-4-hydroxyphenethylene glycol from normetanephrine have been studied in rat brain homogenates. The reaction pathway was shown to be unaffected by several inhibitors of the major (high Km) form of aldehyde reductase such as sodium valproate. Two isoenzymes of aldehyde reductase have been separated and characterized from rat brain. The minor (low Km) isoenzyme is shown to be relatively insensitive to sodium valproate and exhibits a similar inhibitor-sensitivity profile to that obtained for methoxyhydroxyphenethylene glycol formation. The low Km isoenzyme is therefore implicated in catecholamine metabolism. The metabolism of succinic semialdehyde and xylose by rat brain cytosol has also been examined. Aldose metabolism may also be attributed to the action of the low Km reductase, but the existence of a separate succinic semialdehyde reductase is postulated. The possible roles of aldehyde reductases in brain metabolism and the relationship between these enzymes and aldose reductase (alditol: NADP+ 1-oxidoreductase, EC 1.1.1.21) are discussed.

Oxidate-reductive pathways for metabolism of biogenic aldehydes

Publisher Summary This chapter describes oxidative–reductive pathways for metabolism of biogenic aldehydes. In brain and other tissues the aldehydes derived from the catecholamines, that is, the catecholaldehydes, may be either oxidized to the corresponding acid metabolites or reduced to the alcohol derivative. The β-hydroxy-substituted phenylethylamines are more readily reduced, after the initial deamination to produce the aldehyde, than the phenylethylamines which lack the β-hydroxyl group. These findings, coupled with some other observations have shown that norepinephrine and normetanephrine are metabolised primarily to the corresponding alcohol metabolites, whereas the major product of dopamine metabolism in the brain is the acid derivative. These metabolites are formed from the corresponding biogenic aldehyde intermediates by a reductive of oxidative pathway. Evidence has also been obtained which indicates that the NADPH-linked aldehyde reductase, alcohol:NADP oxidoreductase, but not the NADH-dependent enzyme, may be involved in the reduction of biogenic aldehydes including the catecholaldehydes in brain. In one study, it was observed that brain tissue from all classes of vertebrates possessed NADPH-linked aldehyde reductase, whereas, the tiger salamander and American chameleon were devoid of the NADH-linked aldehyde reductase activity.