Enzymology and subcellular localization of aldehyde oxidation in rat liver: Oxidation of 3,4-dihydroxyphenylacetaldehyde derived from dopamine to 3,4-dihydroxyphenylacetic acid

In the presence of ethanol, the metabolism of dopamine in rat liver slices is altered such that the major product is 3,4-dihydroxyphenylethanol, not 3,4-dihydroxyphenylacetic acid (DOPAC). It has been proposed that this metabolic alteration is due to the inhibition of the oxidation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) by acetaldehyde, the first metabolite of ethanol. The oxidation of DOPAL in rat liver slices, however, is not inhibited dramatically by relatively high concentrations of acetaldehyde [A. W. Tank and H. Weiner, Biochem. Pharmac. 28, 3139 (1979)]. Thus, it is possible that acetaldehyde and DOPAL are oxidized by different isozymes of aldehyde dehydrogenase (ALDH) present in different subcellular compartments. Acetaldehyde is oxidized by isozymes of ALDH that are found in the matrix space of the mitochondria of rat liver. The subcellular site of the oxidation of most other aldehydes is not known. Mitochondrial, microsomal and cytosol fractions of the rat liver were isolated by differential centrifugation, and the isozymes of ALDH present in the cytosol and mitochondrial fractions were separated by column isoelectric focusing. Five isozymes of ALDH were isolated from the cytosol, and three isozymes were isolated from the mitochondria. The K_m values for acetaldehyde, p-nitrobenzaldehyde and DOPAL for each of the isolated isozymes were determined and were found to range from approximately 1 μM to 1 mM. Each subcellular fraction was incubated with [ethylamine-2-¹⁴C]dopamine to determine its ability to oxidize DOPAL. Partially purified monoamine oxidase was used to generate DOPAL for those incubations which did not contain mitochondria. Intact mitochondria were capable of oxidizing virtually all the DOPAL to DOPAC in the presence or absence of added pyridine nucleotide coenzymes. Cytosol and microsomal fractions were capable of oxidizing the aldehyde, but not to the same extent as the intact mitochondria. ALDH activity present in the mitochondrial matrix space was inhibited by the addition of rotenone. This treatment inhibited formation of DOPAC by 80 per cent in isolated intact mitochondria in the absence of added pyridine nucleotides. Inclusion of rotenone caused the inhibition of DOPAC formation by ca. 50 per cent when intact mitochondria, microsomes and cytosol were incubated together with dopamine. These results suggest that an isozyme of ALDH present in the mitochondrial matrix space is primarily responsible for the oxidation of DOPAL in rat liver, though nonmitochondrial enzymes can contribute to the oxidation.     

3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease

The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (.OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.OH radicals. These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of alpha-syn should limit DOPAL toxicity.     

Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

BACKGROUND: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation. OBJECTIVE: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes. METHODS: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings. CONCLUSION: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sj?gren-Larsson syndrome, type II hyperprolinemia, gamma-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. Finally, ALDH enzymes display multiple catalytic and non-catalytic functions including ester hydrolysis, antioxidant properties, xenobiotic bioactivation and UV light absorption.     

The role of aldehyde oxidase in drug metabolism

INTRODUCTION: Aldehyde oxidases (AOXs) are molybdo-flavoenzymes with complex evolutionary profiles, as the number and types of active AOX genes vary according to the animal species considered. Humans and higher primates have a single functional AOX1 gene, while rodents are endowed with four AOXs. Along with the endoplasmic cytochrome P450 system (CYP450), cytoplasmic AOX1 is the major enzyme involved in the hepatic phase I metabolism of numerous xenobiotics. AREAS COVERED: The authors review literature to highlight the fact that aldehydes are not the only AOX substrates, as aza- and oxo-heterocycles, that represent the scaffold of many drugs, are also oxidized efficiently by these enzymes. Additionally, the ndefine the different complements of AOX isoenzymes expressed in humans and animal models used in drug metabolism studies and discuss the implications. Furthermore, the authors report on human AOX1 allelic variants that alter the activity of this enzyme. Finally, they discuss the factors of potential importance in controlling the functional activity of AOX1. EXPERT OPINION: There is evidence for an increasing relevance of AOX1 in the metabolism and clearance of new drugs, as measures aiming at controlling CYP450-dependent metabolism of prospective therapeutic agents are becoming routine. This calls for investigations into the biology, catalytic properties and substrate specificity of human AOX1.     

Assessment of the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL)

This work was carried out in order to evaluate the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL). This aldehyde is formed from dopamine (DA) by monoamine oxidases (MAO) and is mainly oxidised to 3,4-dihydroxyphenylacetic acid by brain aldehyde dehydrogenases (ALDH), or eventually reduced to 3,4-dihydroxyphenylethanol by aldose/aldehyde reductases. In vitro, catecholaminergic SH-SY5Y cells were incubated with DA and disulfiram (DSF), an irreversible inhibitor of ALDH. As evidenced by MTT assays, a 24-h treatment with 10(-4) M DA and/or 10(-6) M DSF followed by a 24-h incubation in a drug-free medium evidenced that the toxicity of each of these drugs was potentiated by the second drug. HPLC measurements demonstrated that this drug association induced an early DOPAL production that could result in a delayed cell toxicity. For in vivo studies, male Sprague-Dawley rats were treated with L-DOPA-benserazide, which increases the production of DOPAL by MAO, and DSF. An acute injection of DSF (100mg/kg i.p.) and L-DOPA/benserazide (100mg/kg+25mg/kg, 24h later) significantly increased the DOPAL striatal level. However, a 30-day treatment with DSF (100mg/kg i.p., once every two days) and L-DOPA/benserazide (100mg/kg+25mg/kg, twice a day) did not affect both indexes used to assess the integrity of the nigro-striatal dopaminergic terminals (i.e. the striatal content in DA and the binding to the vesicular monoamine transporter on striatal membranes). These results do not support the hypothesis of a DOPAL toxicity and argue against the toxicity of L-DOPA therapy.     

Effect of triiodothyronine on alcohol dehydrogenase and aldehyde dehydrogenase activities in rat liver. Implications for the control of ethanol metabolism

Treatment of rats with 20 micrograms of 3,3',5-triiodo-L-thyronine (T3) per 100 g body wt for a period of 6 days led to a 45% decrease in total liver alcohol dehydrogenase and a 36% decrease in total liver aldehyde dehydrogenase. Most of the latter decrease was directly attributable to a 57% fall in the level of the physiologically-important low Km mitochondrial isoenzyme. The high Km isoenzyme of the postmitochondrial and soluble fractions was much less affected by T3-treatment. T3, at concentrations up to 0.1 mM, did not inhibit the activity of aldehyde dehydrogenase in vitro. Despite these large losses of the two enzymes most intimately involved in ethanol metabolism, the rate of ethanol elimination in vivo was the same in T3-treated and control animals. Moreover, there was no difference between the two groups in the susceptibility of ethanol elimination to inhibition by 4-methylpyrazole, making it unlikely that an alternative route of ethanol metabolism had been significantly induced by treatment with T3. As it had been suggested that T3 might create a "hypermetabolic state" in which constraints normally imposed on alcohol dehydrogenase and aldehyde dehydrogenase are removed thereby compensating for any loss in total enzymic activity, 2,4-dinitrophenol (0.1 mmoles/kg body wt) was administered to rats in order to raise the general metabolic rate. However, the uncoupler proved to be lethal to T3-treated animals and did not stimulate ethanol elimination in controls. The results do not support the notion that ethanol elimination in vivo is normally governed either by the level of alcohol dehydrogenase or by that of hepatic aldehyde dehydrogenase. However, the mode of control remains unclear.     

Aldehyde toxicity and metabolism: the role of aldehyde dehydrogenases in detoxification,drug resistance and carcinogenesis

Aldehydes are carbonyl compounds found ubiquitously in the environment, derived from both natural and anthropogenic sources. As the aldehydes are reactive species, therefore, they are generally toxic to the body. To reduce the toxicity and pathogenesis related to aldehydes, the human body contains several aldehyde metabolizing enzyme systems including aldehyde oxidases, cytochrome P450 enzymes, aldo-ketoreductases, alcohol dehydrogenases, short-chain dehydrogenases/reductases and aldehyde dehydrogenases (ALDHs). These enzyme systems maintain a low level of aldehydes in the body by catalytically converting them into less-harmful and easily excreted products. The human ALDH (hALDH) superfamily consists of 20 functional ALDH genes identified so far at distinct chromosomal locations, expressing 20 ALDH proteins, which belong to 11 different ALDH families. They are involved in the NAD(P)⁺-dependent oxidation of a wide range of exogenous and endogenous aldehydes to their corresponding carboxylic acids. The hALDHs are present in all sub-cellular locations and have a wide tissue distribution. This review gives an account of aldehydes; their source, toxicity and metabolism, different aldehyde metabolizing enzymes with special emphasis on ALDHs including their biochemical, physiological and pathophysiological roles in the body.     

Ethanol potentiation of carbon tetrachloride hepatotoxicity: possible role for the in vivo inhibition of aldehyde dehydrogenase

A potentiation of CCl4-induced hepatotoxicity was observed in rats pretreated with ethanol 18 hr prior to CCl4 exposure. Hepatic microsomal aldehyde dehydrogenase (ALDH) was significantly inhibited in animals sacrificed 1 hr following the sequential exposure, however, no more so than in those animals receiving CCl4 alone. The animals receiving ethanol alone had ALDH activity similar to vehicle treated controls. Twenty-four hours following a potentiating dose of ethanol and CCl4 an 81 and 57% decline in NAD+-dependent microsomal and mitochondrial ALDH activity was observed, respectively. Similar results were observed for microsomal and mitochondrial NADP+-dependent ALDH activity. The decline in membrane-bound ALDH was greater in potentiated animals than in those receiving CCl4 alone. A relatively smaller decline in cytosolic ALDH activity was observed in CCl4 treated rats with or without ethanol pre-exposure. The data suggest that inhibition of membrane bound ALDH may be one of the major mechanisms of in vivo potentiation of CCl4-induced hepatotoxicity by ethanol.     

Anti-convulsants and brain aldehyde metabolism: Inhibitory characteristics of ox brain aldehyde reductase

The major isoenzyme of aldehyde reductase has been purified from ox brain by affinity chromatography. Carbamazepine (K_i = 7.3 × 10^?4 M) and phenacemide (K_i = 2.5 × 10^?4 M), in common with all other established anti-convulsant drugs tested, have been shown to inhibit the activity of this enzyme. A selection of structural analogues of the anti-convulsant sodium valproate were found to be potent inhibitors of the reductase (K_ivalues in the range 10^?3 M ?5 × 10^?5 M) and these analogues also showed anti-convulsant activity in the mouse maximal electroshock test. A third group of compounds, the flavonoids, constitute the most potent group of aldehyde reductase inhibitors yet reported. Quercetin and morin exhibited K_i values less than 1 μM. The possible relationship between aldehyde metabolism and anti-convulsant action is discussed and structural characteristics pre-disposing to potent inhibition of aldehyde reductase are described.     

Characterization of human erythrocyte aldehyde dehydrogenase

Human erythrocyte aldehyde dehydrogenase was purified to homogeneity. The enzyme exhibited a single band of activity on starch gel electrophoresis and on isoelectric focusing. It was a tetramer with an estimated molecular weight of 230,000 daltons and an isoelectric point of 5.0. Its pH optimum of 8.5, Michaelis-Menten constant for acetaldehyde of 46 microM, and high sensitivity to noncompetitive inhibition by disulfiram resembled human liver cytosolic aldehyde dehydrogenase. Low concentrations of magnesium (5-10 microM) resulted in enhancement of erythrocyte aldehyde dehydrogenase activity, whereas higher physiological concentrations of magnesium resulted in uncompetitive inhibition of enzyme activity. Magnesium inhibited the enzyme activity by increasing the binding of NADH to the enzyme as had been found to be the case for the inhibitory effect of magnesium on the human liver cytosolic enzyme. Erythrocyte aldehyde dehydrogenase may metabolize small amounts of acetaldehyde escaping the liver during ethanol metabolism and protect extrahepatic tissues from acetaldehyde toxicity.     

Disulfiram metabolism as a requirement for the inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase.

In humans and animals, disulfiram produces a disulfiram-ethanol reaction after an ethanol challenge, the basis of which is the inhibition of liver aldehyde dehydrogenase (ALDH). Disulfiram and the metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), and S-methyl-N,N-diethylthiolcarbamate (DETC-Me) were studied in order to determine the role of bioactivation in disulfiram's action as an inhibitor of rat liver mitochondrial low Km ALDH (RLM low Km ALDH). In in vitro studies, disulfiram and DDTC (0.01 to 2.0 mM) both inhibited RLM low Km ALDH in a concentration-dependent manner. The addition of rat liver microsomes to the mitochondrial incubation did not further increase disulfiram-induced RLM low Km ALDH inhibition. However, DDTC-induced RLM low Km ALDH inhibition was increased further, but only at DDTC concentrations less than 0.05 mM. DDTC-Me and DETC-Me (2.0 mM) similarly exhibited an increased RLM low Km ALDH inhibition after the addition of liver microsomes. In in vivo studies, disulfiram (75 mg/kg), DDTC (114 mg/kg), DDTC-Me (41.2 mg/kg) or DETC-Me (18.6 mg/kg) administered i.p. to female rats inhibited RLM low Km ALDH. Inhibition of drug metabolism by pretreatment of rats with the cytochrome P450 inhibitor N-octylimidazole (NOI) (20 mg/kg, i.p.) prior to either disulfiram, DDTC, DDTC-Me or DETC-Me administration blocked the inhibition of RLM low Km ALDH. The in vitro and in vivo data support the conclusion that bioactivation of disulfiram to a reactive chemical species is required for RLM low Km ALDH inhibition and a disulfiram-ethanol reaction.     

Comparing the role of glutathione-S-transferase and mitochondrial aldehyde dehydrogenase in nitroglycerin biotransformation and the correlation with calcitonin gene-related peptide

Both glutathione-S-transferase (GST) and mitochondrial aldehyde dehydrogenase (ALDH-2) have been reported to participate in the biotransformation of nitroglycerin. In this study, we explored which is the major player in nitroglycerin biotransformation. In vivo, rats were treated with nitroglycerin, the blood pressure and plasma calcitonin gene-related peptide (CGRP) were measured. The inhibitor of GST (ethacrynic acid) or ALDH-2 (cyanamide) was given before nitroglycerin treatment; In vitro, the isolated aorta rings were incubated with nitroglycerin to obtain the concentration–response curve. Ethacrynic acid or cyanamide was pre-incubated with the rings before nitroglycerin treatment. The release of CGRP from the aorta rings was determined. Both ethacrynic acid and cyanamide were able to reverse the depressant action of nitroglycerin while the inhibitory effect of cyanamide was more profound. However, combined administration of both inhibitors did not produce an additive effect. The change of plasma CGRP level positively correlated with the change of nitroglycerin-induced hypotensive effects. In the isolated aorta rings, vasodilator responses to nitroglycerin were reduced in the presence of ethacrynic acid or cyanamide while the inhibitory effect of cyanamide was more profound. However, combined administration of both inhibitors did not produce an additive effect. The change of CGRP release from the rings positively correlated with the nitroglycerin-induced vasodilator responses. The present results suggest that both GST and ALDH-2 are involved in nitroglycerin action while ALDH-2 plays a major role, and the change of CGRP contents closely correlates with the biotransformation of nitroglycerin.     

Cyclophosphamide metabolism in the primary immune organs of the chick: Assays of drug activation,P450 expression,and aldehyde dehydrogenase

Several diagnostic catalytic assays were used to determine whether organ-specific metabolic activation or detoxification of cyclophosphamide (CP) contributes to the selective toxicity of CP directed towards differentiating B cells as compared to T cells in the developing chicken. An assay for the alkylation of 4-[p-nitrobenzyl] pyridine (NBP) was used to assess comparative levels of CP activation products generated from microsomal preparations from liver, bursa of Fabricius (B cells), and thymus (T cells) of day-old chicks. Three catalytic assays were used to characterize and compare cytochrome P450-associated enzyme activities in neonatal hepatic and lymphoid tissues. Aldrin epoxidase (AE) was used to detect phenobarbital (PB)-inducible P450 activity. Ethoxyresorufin-O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH) were used for the evaluation of polycyclic aromatic hydrocarbon (PAH)-inducible P450 activities in control and PB- or 3,3',4,4'-tetrachlorobiphenyl (TCB)-induced animals. Using the NBP assay, basal and PB-induced CP activation were observed using chick liver microsomes. However, no evidence of CP activation from immune organ microsomes was observed in control, PB-, or TCB-induced chicks. Basal and PB-induced AE activities were observed in thymus, but not bursa, and represented less than 1% of basal liver activity. EROD activity was detected in TCB-induced samples from both thymus and bursa, the thymus having the greater activity. Activities of aldehyde dehydrogenase (ALDH), an enzyme involved in CP detoxification, were about equal in cytosolic fractions from the bursa and thymus. These studies suggest strongly that tissue-specific differences in metabolic capacities are not the major factors governing the selective toxicity of CP directed towards differentiating B lymphocytes in vivo.     

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.     

Molecular genetics of human aldehyde dehydrogenase.

Four non-allelic genes, which encode four different aldehyde dehydrogenase (ALDH) isozymes, have been cloned and characterized at the present time. The coding nucleotide sequences, and organization of introns and exons of these genes have been elucidated. The ALDH1 gene encodes the major cytosolic ALDH1 existing in the liver and other tissues. The genetic deficiency of this isozyme was found at a low frequency (< 10%) in both Caucasians and Orientals. The deficiency and alcohol sensitivity character are inherited together in one large Caucasian family examined. The ALDH1 gene contains two hormone response elements in its upstream 5' region. The ALDH2 gene encodes the major liver mitochondrial ALDH2 which has a very low Km for acetaldehyde. The atypical ALDH2(2) allele is common (about 30%) in Orientals; and subjects with ALDH2(2) allele, both homozygous and heterozygous status, lack ALDH activity. These individuals are alcohol sensitive and have a markedly reduced risk in developing alcoholism and alcoholic liver diseases. The ALDH3 gene produces a cytosolic ALDH3 isozyme existing in the stomach and liver carcinoma but hardly in normal liver. The ALDH3 locus is polymorphic in Orientals and presumably other populations. The ALDH5 gene, which is expressed in testes and liver, is highly polymorphic in both Caucasians and Orientals. The variation of these two loci may affect the development of alcohol-related problems.     

3,4-亚甲基二氧基甲基苯丙胺对大鼠的神经毒性及维生素C的保护作用

目的:探讨3,4-亚甲基二氧基甲基苯丙胺(MDMA)的神经毒性机制及抗氧化剂维生素C是否具有MDMA神经毒性的保护作用.方法:雄性Wistar大鼠随机分为正常对照组、MDMA组、MDMA给药前30 min给予维生素C组、MDMA给药后3 h给予维生素C组、MDMA给药后5 h给予维生素C组,MDMA和维生素C均为单剂量腹腔注射,剂量分别为20和250 mg·kg-1.1周后采用高效液相色谱法测定海马、枕叶皮层5-羟色胺(5-HT)的含量,原位杂交方法检测SERTmRNA,免疫组织化学法检测GFAP蛋白.结果:与正常对照组比较,MDMA组大鼠枕叶皮层、海马5-HT含量均明显下降(P<0.05),大鼠海马SERTmRNA的表达明显下降(P<0.05),而脑组织GFAP蛋白的表达显著升高(P<0.05).与MDMA组比较,提前30 min和MDMA后3 h给予维生素C两组的5-HT含量和海马SERTmRNA的表达无明显改变(P>0.05),而给予MDMA后5 h给予维生素C组的5-HT含量和海马SERTmRNA的表达明显增加(P<0.05);不同时间给予维生素C的3组大鼠脑组织GFAP蛋白的表达均较MDMA组显著降低(P<0.05).结论:MDMA对中枢5-HT系统具有明显的神经毒性;在给予MDMA后5 h给予维生素C对5-HT能系统有保护作用.     

线粒体醛脱氢酶对心脏保护作用的研究进展

线粒体醛脱氢酶(ALDH2)是醛脱氢酶的亚型之一,具有脱氢酶和酯酶等多种酶功能。体内乙醇、氨基酸、生物胺、维生素、类固醇及脂质的代谢过程中会产生众多醛类物质。ALDH2在辅助因子NAD(P)+的参与下将醛类物质脱氢成为相应的羧酸,对减轻醛类物质对机体的毒性作用具有重要意义。ALDH2发挥酯酶功能则不需要辅助因子,可将羧酸酯或者其他酸转化为相应的羧酸和醇。近年的研究表明,ALDH2酶活性的下降将加重酒精、缺血等多种因素引起的心肌损伤和促进硝酸甘油耐受的发生,因此针对ALDH2开发和研制特异性激动剂,将为心脏疾病的药物防治提供新思路。     

The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity

3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are ring-substituted amphetamine derivatives with stimulant and hallucinogenic properties. The recreational use of these amphetamines, especially MDMA, is prevalent despite warnings of irreversible damage to the central nervous system. MDA and MDMA are primarily serotonergic neurotoxicants. Because (1) neither MDA nor MDMA produces neurotoxicity when injected directly into brain, (2) intracerebroventricular (i.c.v.) administration of some major metabolites of MDA and MDMA fails to reproduce their neurotoxicity, (3) alpha-methyldopamine (alpha-MeDA) and N-methyl-alpha-MeDA are metabolites of both MDA and MDMA, (4) alpha-MeDA and N-methyl-alpha-MeDA are readily oxidized to the corresponding ortho-quinones, which can undergo conjugation with glutathione (GSH), and (5) quinone thioethers exhibit a variety of toxicologic activities, we initiated studies on the potential role of thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA in the neurotoxicity of MDA and MDMA. Our studies have revealed that the thioether conjugates stimulate the acute release of serotonin, dopamine, and norepinephrine and produce a behavioral response commensurate with the "serotonin syndrome." Direct injection of the conjugates into rat brain also produces long-term depletions in serotonin (5-HT) concentrations, elevations in GFAP expression, and activation of microglial cells. The data are consistent with the view that thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA contribute to the neurotoxicity of the parent amphetamines.