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PubMed2006

Neurotoxicity of reactive aldehydes: the concept of "aldehyde load" as demonstrated by neuroprotection with hydroxylamines.

The concept of "oxidative stress" has become a mainstay in the field of neurodegeneration but has failed to differentiate critical events from epiphenomena and sequalae. Furthermore, the translation of current concepts of neurodegenerative mechanisms into effective therapeutics for neurodegenerative diseases has been meager and disappointing. A corollary of current concepts of "oxidative stress" is that of "aldehyde load". This relates to the production of reactive aldehydes that covalently modify proteins, nucleic acids, lipids and carbohydrates and activate apoptotic pathways. However, reactive aldehydes can also be generated by mechanisms other than "oxidative stress". We therefore hypothesized that agents that can chemically neutralize reactive aldehydes should demonstrate superior neuroprotective actions to those of free radical scavengers. To this end, we evaluated hydroxylamines as aldehyde-trapping agents in an in vitro model of neurodegeneration induced by the reactive aldehyde, 3-aminopropanal (3-AP), a product of polyamine oxidase metabolism of spermine and spermidine. In this model, the hydroxylamines N-benzylhydroxylamine, cyclohexylhydroxylamine and t-butylhydroxylamine were shown to protect, in a concentration-dependent manner, against 3-AP neurotoxicity. Additionally, a therapeutic window of 3 h was demonstrated for delayed administration of the hydroxylamines. In contrast, the free radical scavengers TEMPO and TEMPONE and the anti-oxidant ascorbic acid were ineffective in this model. Extending these tissue culture findings in vivo, we examined the actions of N-benzylhydroxylamine in the trimethyltin (TMT) rat model of hippocampal CA3 neurodegeneration. This model involves augmented polyamine metabolism resulting in the generation of reactive aldehydes that compromise mitochondrial integrity. In the rat TMT model, NBHA (50 mg/kg, sc, daily) provided 100% protection against neurodegeneration, as reflected by measurements of KCl-evoked glutamate release from hippocampal brain slices and septal high affinity glutamate uptake. In contrast, ascorbic acid (100 mg/kg, sc, daily) failed to protect CA3 neurons from TMT toxicity. In summary, our data support further evaluation of the concept of "aldehyde load" in neurodegeneration and the potential clinical investigation of agents that are effective traps for reactive aldehydes.

Aldehydes↗
PubMed1997

Mechanism-based inactivation of cytochrome P450 2B4 by aldehydes: relationship to aldehyde deformylation via a peroxyhemiacetal intermediate.

The inactivation of cytochrome P450 2B4 by aldehydes in a reconstituted enzyme system requires molecular oxygen and NADPH and is not prevented by the addition of catalase, superoxide dismutase, epoxide hydrolase, glutathione, or ascorbic acid. A strong correlation between loss of enzymatic activity and bleaching of the heme chromophore was established, and the inactivation was shown to be irreversible upon dialysis. In general, saturated aldehydes are more inhibitory than those with alpha,beta-unsaturation, as indicated by the k(inact) values, and primary aldehydes are more potent inactivators than the structurally related secondary and tertiary aldehydes. Consistent with recent studies on catalytic specificity of the T302A mutant of this cytochrome [Vaz, A. D. N., Pernecky, S. J., Raner, G. M., & Coon, M. J. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 4644-4648], the rate of aldehyde deformylation, as determined by formation of the alcohol with one less carbon atom, is greatly stimulated over that of the wild-type enzyme. Of particular interest, the rate of oxidation of aldehydes to carboxylic acids is decreased with the mutant, whereas the rate of inactivation via heme destruction is enhanced. Furthermore, comparative deuterium isotope effects and the relative rates of inactivation and product formation suggest that the mechanism of aldehyde inactivation of P450 2B4 involves the deformylation reaction and is unrelated to carboxylic acid formation. Finally, in the reaction of P450 2B4 with 3-phenylpropionaldehyde, the formation of a heme adduct with a molecular weight corresponding to that of native heme plus 104 mass units confirms the loss of the carbonyl group from the aldehyde prior to reaction with the chromophore. We conclude that inactivation of P450 by aldehydes occurs via homolytic cleavage of a peroxyhemiacetal intermediate to give an alkyl radical that reacts with the heme.

Aldehydes↗
PubMed1994

Metabolic engineering of glycine betaine synthesis: plant betaine aldehyde dehydrogenases lacking typical transit peptides are targeted to tobacco chloroplasts where they confer betaine aldehyde resistance.

Certain higher plants synthesize and accumulate glycine betaine, a compound with osmoprotectant properties. Biosynthesis of glycine betaine proceeds via the pathway choline-->betaine aldehyde-->glycine betaine. Plants such as tobacco (Nicotiana tabacum L.) which do not accumulate glycine betaine lack the enzymes catalyzing both reactions. As a step towards engineering glycine betaine accumulation into a non-accumulator, spinach and sugar beet complementary-DNA sequences encoding the second enzyme of glycine-betaine synthesis (betaine aldehyde dehydrogenase, BADH, EC 1.2.1.8) were expressed in tobacco. Despite the absence of a typical transit peptide, BADH was targeted to the chloroplast in leaves of transgenic plants. Levels of extractable BADH were comparable to those in spinach and sugar beet, and the molecular weight, isoenzyme profile and Km for betaine aldehyde of the BADH enzymes from transgenic plants were the same as for native spinach or sugar beet BADH. Transgenic plants converted supplied betaine aldehyde to glycine betaine at high rates, demonstrating that they were able to transport betaine aldehyde across both the plasma membrane and the chloroplast envelope. The glycine betaine produced in this way was not further metabolized and reached concentrations similar to those in plants which accumulate glycine betaine naturally. Betaine aldehyde was toxic to non-transformed tobacco tissues whereas transgenic tissues were resistant due to detoxification of betaine aldehyde to glycine betaine. Betaine aldehyded ehydrogenase is therefore of interest as a potential selectable marker, as well as in the metabolic engineering of osmoprotectant biosynthesis.

Aldehyde Oxidoreductases↗
PubMed1991

Lipid aldehyde oxidation as a physiological role for class 3 aldehyde dehydrogenases.

A large number of different unsaturated, saturated and hydroxylated aliphatic aldehydes can be generated during the peroxidation of cellular lipids. This study examined the kinetic properties of purified Class 3 rat aldehyde dehydrogenase (ALDH) with respect to the oxidation of various lipid aldehyde substrates. It also compared the substrate preference of the prototypic Class 3 ALDH with that of the constitutive rat microsomal aldehyde dehydrogenase. The results suggest that (1) microsomal ALDH is a member of the Class 3 aldehyde dehydrogenase family, and (2) the physiological role of the Class 3 ALDHs, including the microsomal form, is the oxidation of medium (6 to 9 carbon) chain length saturated and unsaturated aldehydes generated by the peroxidation of cellular lipids. Short chain aliphatic aldehydes, such as a malondialdehyde and 4-hydroxyalkenals, are not substrates for the Class 3 aldehyde dehydrogenases.

Aldehyde Dehydrogenase↗
PubMed1997

Substrate inhibition by betaine aldehyde of betaine aldehyde dehydrogenase from leaves of Amaranthus hypochondriacus L.

We have previously proposed that at low substrate concentrations betaine aldehyde dehydrogenase follows an irreversible Iso Ordered Bi Bi Steady State kinetic mechanism with NAD+ as the leading substrate [E.M. Valenzuela-Soto and R.A. Muñoz-Clares, J. Biol. Chem. 268 (1993) 23818-23823]. To further the understanding of this enzyme, we have studied the kinetics at high substrate concentrations. Betaine aldehyde at concentrations above 500 microM behaves as a non-competitive inhibitor against NAD+, with downward-curved slope and intercept replots. Double-inhibition studies, using NADH as the second inhibitor, show the formation of the abortive ternary complex enzyme NADH betaine aldehyde, from which NADH may escape at a finite rate, accounting for the nonlinear Dixon plots obtained for both inhibitors. In addition, the binary complex enzyme x betaine aldehyde may give rise to a slower alternative route of reaction, which, under our experimental conditions, was observed at NAD+ concentrations above 1 mM, where double-reciprocal plots of initial velocity against [NAD+] and Dixon plots of 1/v against [NADH] were concave downward. In contrast with other aldehyde dehydrogenases, no 'substrate activation' by the aldehyde was observed under several conditions, which is consistent with the alternative route of reaction being slower than the route which operates at low substrate concentrations. Taken together, our results are consistent with the partial inhibition by high betaine aldehyde concentrations resulting from an irreversible Iso Random Steady State mechanism with a preferential route of reaction. Eventually, at very high betaine aldehyde concentrations, the kinetic mechanism may change to an apparent Ping Pong.

Aldehyde Oxidoreductases↗
PubMed1996

Kinetics and specificity of human liver aldehyde dehydrogenases toward aliphatic, aromatic, and fused polycyclic aldehydes.

Human mitochondrial aldehyde dehydrogenase (ALDH-2) has a Km for acetaldehyde that is 900-fold lower than that for the cytosolic isozyme, ALDH-1. An increase in aliphatic aldehyde chain length decreases the ALDH-2 Km by up to 10-fold but decreases that of ALDH-1 by 5 orders of magnitude. As a consequence, the Km of ALDH-1 for decanal is 8 times lower than that of ALDH-2, i.e. 2.9 +/- 0.4 and 22 +/- 3 nM, respectively. Determination of these low Km values required kinetic analysis of the simultaneous enzymatic conversion of two aldehyde substrates, an approach also applied to aromatic and fused polycyclic aldehydes. For most of these substrates, maximum velocities are 5-100 times lower than those for acetaldehyde. Addition of one of these tight-binding, slow-turnover substrates to a reaction mixture containing ALDH, NAD+, and a "reference" aldehyde substrate (e.g. acetaldehyde) blocks the principal (reference) enzymatic reaction temporarily and reversibly. Once the first substrate is converted to product, the enzyme can act on the reference substrate. In terms of apparent affinity and blocking capacity, naphthalene and phenanthrene aldehydes were the most potent effectors. Other aromatic and fused polycyclic and heterocyclic aldehydes, as well as derivatives of coumarin, quinoline, indole, and pyridine, are tight-binding, slow-turnover substrates for ALDH-2 and relatively weak inhibitors of ALDH-1. The hydrophobicity of substituents of benzaldehydes, and particularly of naphthaldehydes, correlates with their binding constants toward ALDH-2. Vitamin A1 aldehydes are specific natural substrates for ALDH-1; at pH 7.5, for all-trans- and 13-cis-retinal, Km = 1.1 and 0.37 micromolar, respectively, and kcat/Km is 50-100 times higher than that for acetaldehyde. At the same time, the retinals are inhibitors of ALDH-2, all-trans-retinal being a particularly potent inhibitor (competitive Ki = 43 nM, noncompetitive Ki = 316 nM). These properties suggest that all-trans-retinal is a possible regulatory compound for ALDH-2 in vivo. The data in general point to specialized roles for both major human liver ALDH isozymes in the oxidation of bulky/hydrophobic natural compounds, with Km values in the low nanomolar range.

Acetaldehyde↗
PubMedDate not supplied

Aldehyde dehydrogenase and aldehyde reductase in isolated bovine brain microvessels.

The activities of aldehyde dehydrogenase and aldehyde reductase were measured in microvessel fractions isolated from bovine brain. Aldehyde dehydrogenase specific activity in microvessels was enriched 1.5-fold over that measured in grey matter. The specific activity of aldehyde reductase was significantly lower in parenchymal vessles and microvessels than in grey matter. The presence of aldehyde dehydrogenase and aldehyde reductase in cerebral microvasculature is consistent with previous reports of enrichment of other enzymes involved in synthesis and degradation of monoamines. The enrichment of aldehyde dehydrogenase in cerebral microvasculature provides additional evidence for an enzymatic blood-brain barrier for biogenic aldehydes or ethanol-derived acetaldehyde.

Acetaldehyde↗
PubMed1998

Human neutrophils employ myeloperoxidase to convert alpha-amino acids to a battery of reactive aldehydes: a pathway for aldehyde generation at sites of inflammation.

We have recently demonstrated that activated phagocytes employ the heme protein myeloperoxidase, H2O2, and Cl- to oxidize the aromatic amino acid l-tyrosine to the reactive aldehyde p-hydroxyphenylacetaldehyde. We now present evidence for the generality of this reaction by demonstrating that neutrophils employ the myeloperoxidase-H2O2-Cl- system to oxidize nearly all of the common alpha-amino acids to yield a family of reactive aldehydes. Chemical characterization suggested that reactive carbonyl moieties were generated during amino acid oxidation by myeloperoxidase. The structures of amino-acid-derived aldehydes were confirmed using a variety of mass spectrometric methods. Aldehyde production required myeloperoxidase, H2O2, Cl-, and an amino acid; it was inhibited by heme poisons and catalase. Hypochlorous acid was the apparent oxidizing intermediate because its addition to alpha-amino acids resulted in the formation of the anticipated aldehyde. Stimulated human neutrophils likewise generated aldehydes from all classes of alpha-amino acids by a pathway inhibited by heme poisons and catalase, implicating myeloperoxidase and H2O2 in the cell-mediated reaction. Aldehyde production accounted for a significant fraction of the H2O2 generated by stimulated neutrophils at physiological concentrations of amino acids. Collectively, these results suggest that amino-acid-derived aldehydes represent a product of reactive oxidant species generated by activated phagocytes.

Aldehydes↗
PubMed1991

Human aldehyde dehydrogenase. Activity with aldehyde metabolites of monoamines, diamines, and polyamines.

Two isozymes (E1 and E2) of human aldehyde dehydrogenase (EC 1.2.1.3) were purified to homogeneity 13 years ago and a third isozyme (E3) with a low Km for gamma-aminobutyraldehyde only recently. Comparison with a variety of substrates demonstrates that substrate specificity of all three isozymes is broad and similar. With straight chain aliphatic aldehydes (C1-C6) the Km values of the E3 isozyme are identical with those of the E1 isozyme. All isozymes dehydrogenate naturally occurring aldehydes, 5-imidazoleacetaldehyde (histamine metabolite) and acrolein (product of beta-elimination of oxidized polyamines) with similar catalytic efficiency. Differences between the isozymes are in the Km values for aminoaldehydes. Although all isozymes can dehydrogenate gamma-aminobutyraldehyde, the Km value of the E3 isozyme is much lower: the same appears to apply to aldehyde metabolites of cadaverine, agmatine, spermidine, and spermine for which Km values range between 2-18 microM and kcat values between 0.8-1.9 mumol/min/mg. Thus, the E3 isozyme has properties which make it suitable for the metabolism of aminoaldehydes. The physiological role of E1 and E2 isozymes could be in dehydrogenation of aldehyde metabolites of monoamines such as 3,4-dihydroxyphenylacetaldehyde or 5-hydroxyindoleacetaldehyde; the catalytic efficiency with these substrates is better with E1 and E2 isozymes than with E3 isozyme. Isoelectric focusing of liver homogenates followed by development with various physiological substrates together with substrate specificity data suggest that aldehyde dehydrogenase (EC 1.2.1.3) is the only enzyme in the human liver capable of catalyzing dehydrogenation of aldehydes arising via monoamine, diamine, and plasma amine oxidases. Although the enzyme is generally considered to function in detoxication, our data suggest an additional function in metabolism of biogenic amines.

Aldehyde Dehydrogenase↗
PubMed1990

Aldehyde-oxidizing enzymes in an adult moth: in vitro study of aldehyde metabolism in Heliothis virescens.

The conversion of pheromonal aldehydes to carboxylic acids in vitro in tissue extracts of Heliothis virescens is catalyzed by both aldehyde dehydrogenase and aldehyde oxidase enzymes. The aldehyde-oxidizing activity in antennae, heads, legs, and hemolymph from male and female moths was examined by radiochromatographic and spectroscopic assays. First, the enzymatic activity was measured in the presence or absence of added NAD+ using either (Z)-9-tetradecenal or (Z)-11-hexadecenal as tritiated substrate. Second, substrate specificity was determined spectroscopically by (i) indirect measurement of the AO-released hydrogen peroxide through the coupled AO-horseradish peroxidase reaction and by (ii) direct measurement of the ALDH-produced NADH. Both aldehyde-oxidizing activities were associated with soluble enzymes in the antennal extracts, and these enzymes degraded pheromone and nonpheromonal aldehydes. Both AO and ALDH activities were present in male and female tissues. AO activity was exhibited primarily in the antennal extracts and to a lesser degree in the leg extracts. Moreover, ALDH activity was distributed in the antenna, head, and leg extracts. A vinyl ketone analog of (Z)-11-hexadecenal preferentially inhibited the ALDH activity over the AO activity.

Aldehyde Dehydrogenase↗
PubMed2000

Aromatic aldehydes as fluorogenic indicators for human aldehyde dehydrogenases and oxidases: substrate and isozyme specificity.

Substrate properties of a number of potentially fluorogenic aromatic aldehydes of naphthalenes, phenanthrenes and anthracenes and of some coumarin aldehydes towards various forms of the human and rat aldehyde oxidase and dehydrogenase were examined using absorption and emission spectroscopy. It was demonstrated that recombinant human class 1 aldehyde dehydrogenase (ALDH-1) readily oxidizes naphthalene (except for those ortho-substituted), phenanthrene and coumarin aldehydes, whereas the class 3 enzyme (ALDH-3) from human saliva is active only towards 2-naphthaldehyde derivatives. The observed reaction rates in both cases are comparable to those of the best known substrates, and the Km values are typically in the sub-micromolar range. Aldehyde oxidases (AlOx), which are present in mammalian liver, reveal much broader substrate specificity, oxidizing nearly all the compounds examined, including those of the anthracene series, with maximum activity in the micromolar range of substrate concentration. In rat liver, nearly all AlOx activity was located in the cytosolic fraction.

Aldehyde Dehydrogenase↗
PubMed2006

Aldehyde load in ischemia-reperfusion brain injury: neuroprotection by neutralization of reactive aldehydes with phenelzine.

In ongoing studies of the neuroprotective properties of monoamine oxidase inhibitors, we found that phenelzine provided robust neuroprotection in the gerbil model of transient forebrain ischemia, with drug administration delayed up to 3 h post reperfusion. Since ischemia-reperfusion brain injury is associated with large increases in the concentrations of reactive aldehydes in the penumbra area, we investigated if the hydrazine function of phenelzine was capable of sequestering reactive aldehydes. Both aminoaldehydes and acrolein are generated from the metabolism of polyamines to putrescine by polyamine oxidase. These toxic aldehydes in turn compromise mitochondrial and lysosomal integrity and initiate apoptosis and necrosis. Previous studies have demonstrated that pharmacological neutralization of reactive aldehydes via the formation of thioacetal derivatives results in significant neuroprotection in ischemia-reperfusion injury, in both focal and global ischemia models. In our studies of acrolein and 3-aminopropanal toxicity, using an immortalized retinal cell line, we found that aldehyde sequestration with phenelzine was neuroprotective. The neuroprotection observed with phenelzine is in agreement with previous studies of aldehyde sequestering agents in the treatment of ischemia-reperfusion brain injury and supports the concept that "aldehyde load" is a major factor in the delayed cell losses of the ischemic penumbra.

Acrolein↗
PubMed2006

Critical aspects of the determination of pentafluorobenzyl derivatives of aldehydes by gas chromatography with electron-capture or mass spectrometric detection: Validation of an optimized strategy for the determination of oxygen-related odor-active aldehydes in wine.

This work presents a thorough study of some aspects critical to the quantitative performance of methods for the determination of volatile aldehydes previously derivatized to pentafluorobenzyl hydroxylamine oximes. The conclusions of the study are further applied to the validation of an optimized procedure for the determination of oxidation-related aldehydes from wine. Aspects studied include the chromatographic injection, the analytical performance of electron-capture detection (ECD) or MS detection, and the way in which the derivatization is carried out. Different injection techniques have been optimized and compared (classical splitless-hot injection; cold splitless; and large volume solvent split injection). All of them were carried out in a programmed temperature vaporization (PTV) injector, with a 350 microL internal volume liner (3.4 mm internal diameter). Classical splitless injection of hexane extracts is troublesome and requires large carrier gas flows (>10 mL min(-1)). Cold splitless injection was clearly superior. Large volume solvent split injection has been also optimized. ECD has been found to lack the necessary selectivity for the determination of unsaturated aldehydes in wine, although the quantitation of several minor aldehydes is possible. MS detection has proven to be superior for the determination of these compounds in wine. The way in which the reagent is applied is also critical and for the case of wine is important to ensure that the reagent is applied after some of the major wine aldehydes have been eliminated. The finally proposed method is extremely sensitive. Method detection limits ranged from 0.002 microg L(-1) (for unsaturated aldehydes) to 0.73 microg L(-1) (for phenylacetaldehyde) and precision (measured as relative standard deviation) is < or =6% in all cases. The method makes it possible to determine quantitatively in a single run the wine aldehydes with sensory significance (isobutyraldehyde, 2-methylbutanal, isovaleraldehyde, (E)-2-hexenal, (E)-2-heptenal, (E)-2-octenal, (E)-2-nonenal, methional and phenylacetaldehyde).

Aldehydes↗
PubMed1983

The kinetics and mechanism of pig-liver aldehyde reductase. Comparative studies with pyridine-3-aldehyde and p-carboxybenzaldehyde.

Initial-rate measurements were made of the reduction of pyridine-3-aldehyde and p-carboxybenzaldehyde by NADPH catalyzed by pig liver aldehyde reductase I. The initial velocity analysis and product inhibition data suggest that aldehyde reductase I obeys a compulsory-order mechanism with pyridine-3-aldehyde as substrate but follows a partially random-order pathway with p-carboxybenzaldehyde. The partially random-order pathway would be operative only at high concentrations of p-carboxybenzaldehyde. In both cases, aldehydes and the corresponding alcohol substrates inhibit the enzyme at high concentration. Abortive ternary complexes are shown to be formed with pyridine-3-aldehyde and with p-carboxybenzaldehyde. Dissociation of the coenzyme from the abortive ternary complex seems only to be observed with p-carboxybenzaldehyde. This study suggests overall that an enzyme kinetic mechanism may be different, depending on whether specific interactions can occur between certain amino acid residue(s) of the protein active site and substrates. Finally, the mechanism of the inhibition of pyridine-3-aldehyde reduction by diacid derivatives is discussed.

Alcohol Oxidoreductases↗
PubMed1994

Effects of changing glutamate 487 to lysine in rat and human liver mitochondrial aldehyde dehydrogenase. A model to study human (Oriental type) class 2 aldehyde dehydrogenase.

Many Oriental people possess a liver mitochondrial aldehyde dehydrogenase where glutamate at position 487 has been replaced by a lysine, and they have very low levels of mitochondrial aldehyde dehydrogenase activity. To investigate the cause of the lack of activity of this aldehyde dehydrogenase, we mutated residue 487 of rat and human liver mitochondrial aldehyde dehydrogenase to a lysine and expressed the mutant and native enzyme forms in Escherichia coli. Both rat and human recombinant aldehyde dehydrogenases showed the same molecular and kinetic properties as the enzyme isolated from liver mitochondria. The E487K mutants were found to be active but possessed altered kinetic properties when compared to the glutamate enzyme. The Km for NAD+ at pH 7.4 increased more than 150-fold, whereas kcat decreased 2-10-fold with respect to the recombinant native enzymes. Detailed steady-state kinetic analysis showed that the binding of NAD+ to the mutant enzyme was impaired, and it could be calculated that this resulted in a decreased nucleophilicity of the active site cysteine residue. The rate-limiting step for the rat E487K mutant was also different from that of the recombinant rat liver aldehyde dehydrogenase in that no pre-steady-state burst of NADH formation was found with the mutant enzyme. Both the rat native enzyme and the E487K mutant oxidized chloroacetaldehyde twice as fast as acetaldehyde, indicating that the rate-limiting step was not hydride transfer or coenzyme dissociation but depended upon nucleophilic attack. Each enzyme form showed a 2-fold activation upon the addition of Mg2+ ions. Substituting a glutamine for the glutamate did not grossly affect the properties of the enzyme. Glutamate 487 may interact directly with the positive nicotinamide ring of NAD+ for the Ki of NADH was the same in the lysine enzyme as it was in the glutamate form. Because of the altered NAD+ binding properties and kcat of the E487K variant, it is assumed that people possessing this form will not have a functional mitochondrial aldehyde dehydrogenase.

Aldehyde Dehydrogenase↗
PubMed1982

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-Km aldehyde dehydrogenase activity was markedly decreased by all three drugs after 2 and 24 hr whereas only cyanamide inhibited the high-Km 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.

Aldehyde Dehydrogenase↗