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PubMed1982

Stimulation of ammonia and 2-oxoglutarate-dependent o(2) evolution in isolated chloroplasts by dicarboxylates and the role of the chloroplast in photorespiratory nitrogen recycling.

Intact chloroplasts isolated from spinach (Spinacia oleracea L.) leaves showed a light-dependent O(2) evolution (5.5 +/- 0.75 micromoles per milligram chlorophyll per hour) when supplied with ammonia and 2-oxoglutarate. This (ammonia, 2-oxoglutarate)-dependent O(2) evolution was stimulated 2- to 4-fold by the dicarboxylates, malate, succinate, fumarate, glutarate, and l-tartarate. Evolution of O(2) in the presence of malate was dependent on the presence of both 2-oxoglutarate and NH(4)Cl; malate with only either 2-oxoglutarate and NH(4)Cl alone did not support O(2) evolution. Furthermore, in the presence of malate, the amount of O(2) evolved was solely dependent on the amount of NH(4)Cl or 2-oxoglutarate added and malate did not affect the ratio of O(2) evolved to NH(4)Cl or 2-oxoglutarate consumed. Studies with inhibitors (2-(3,4-dichlorophenyl)-1,1-dimethyl urea, methionine sulfoximine, and azaserine) indicated that the above activity was directly linked to glutamine synthetase and glutamate synthase activity in the chloroplast and was not caused by the metabolism of malate. The V(max)/2 of (ammonia, 2-oxoglutarate)-dependent O(2) evolution was reached at 32 micromolar NH(4)Cl and 6 millimolar (approximately) 2-oxoglutarate in the absence of malate, and at 22 micromolar NH(4)Cl and 73 micromolar 2-oxoglutarate when malate (3 millimolar) was present.Intact chloroplasts isolated from pea (Pisum sativum) leaves also showed a stimulation of (ammonia, 2-oxoglutarate)-dependent O(2) evolution by malate. However glutamine was required for this activity even though glutamine with only either NH(4)Cl or 2-oxoglutarate did not respond to malate stimulation.The measured rates of (ammonia, 2-oxoglutarate)-dependent O(2) evolution in isolated spinach chloroplasts in the presence of malate were about 19.5 +/- 4.5 micromoles O(2) evolved per milligram chlorophyll per hour. This is adequate to sustain photorespiratory NH(3) recycling and the refixation of NH(3) arising from NO(3) under ambient conditions in the light. The role of the chloroplast in photorespiratory NH(3) recycling and the nature of the associated transport of 2-oxoglutarate into the chloroplast is discussed.

Journal Article↗
PubMed1983

Effect of inhibitors on ammonia-, 2-oxoglutarate-, and oxaloacetate-dependent o(2) evolution in illuminated chloroplasts.

The evolution of O(2) in spinach chloroplasts in the presence of oxaloacetate (OAA) was inhibited by a wide range of dicarboxylates. In contrast, (ammonia, 2-oxoglutarate)-dependent O(2) evolution was stimulated by malate, succinate, fumarate, glutarate, maleiate, and l-tartrate although OAA has little effect. This increase in O(2) evolution was accompanied by a similar increase in (14)C incorporation from [5-(14)C]oxoglutarate into amino acids which was sensitive to azaserine inhibition. Glutamate and aspartate inhibited (ammonia, 2-oxoglutarate)-dependent O(2) evolution, but this inhibition was relieved by the addition of succinate, malate, or fumarate. OAA-dependent O(2) evolution also was inhibited by glutamate and aspartate, but succinate, malate, or fumarate had little effect on this inhibition. Phthalonate and n-butyl malonate inhibited (ammonia, 2-oxoglutarate)-dependent O(2) evolution competitively with respect to 2-oxoglutarate and uncompetitively with respect to malate. Both these inhibitors inhibited OAA-dependent O(2) evolution competitively. This evidence suggests that different mechanisms might be involved in the transport of OAA, 2-oxoglutarate, and malate into the chloroplasts.

Journal Article↗
PubMed1983

Characterization of dicarboxylate stimulation of ammonia, glutamine, and 2-oxoglutarate-dependent o(2) evolution in isolated pea chloroplasts.

Intact isolated chloroplasts from pea (Pisum sativum) leaves carried out light-dependent (NH(3), 2-oxoglutarate) and (glutamine, 2-oxoglutarate)-dependent O(2) evolution at rates of 3.3 +/- 0.7 (n = 7) and 6.0 +/- 0.4 (n = 5) micromoles per milligram chlorophyll per hour, respectively. Malate stimulated the rate of (NH(3), 2-oxoglutarate)-dependent O(2) evolution 2.1 +/- 0.5 (n = 7)-fold in the absence of glutamine, and 3.3 +/- 0.4 (n = 11)-fold in the presence of glutamine. Malate also stimulated (glutamine, 2-oxoglutarate)-dependent O(2) evolution in the presence of high concentrations of glutamine. The affinity (K(1/2)) of (NH(3), glutamine, 2-oxoglutarate)-dependent O(2) evolution for 2-oxoglutarate was estimated at 200 to 250 micromolar in the absence of malate and 50 to 80 micromolar when malate (0.5 millimolar) was present. In contrast to malate and various other dicarboxylates, aspartate, glutarate, and glutamate did not stimulate (NH(3), glutamine, 2-oxoglutarate)-dependent O(2) evolution in isolated pea chloroplasts. Using both in vitro assays and reconstituted chloroplast systems, malate was shown to have no effect on the activities of either glutamine synthetase or glutamate synthase.The concentration of malate required for maximal stimulation of O(2) evolution was dependent on the concentration of 2-oxoglutarate present. However, the small extent of the competition between malate and 2-oxoglutarate for uptake was not consistent with that predicted by the current ;single carrier' model proposed for the uptake of dicarboxylates into chloroplasts.

Journal Article↗
PubMed1984

Respiration during Postharvest Development of Soursop Fruit, Annona muricata L.

Fruit of soursop, Annona muricata L., showed increased CO(2) production 2 days after harvest, preceding the respiratory increase that coincided with autocatalytic ethylene evolution and other ripening phenomena. Experiments to alter gas exchange patterns of postharvest fruit parts and tissue cylinders had little success.The respiratory quotient of tissue discs was near unity throughout development. 2,4-Dinitrophenol uncoupled respiration more effectively than carbonylcyanide m-chlorophenylhydrazone; 0.4 millimolar KCN stimulated, 4 millimolar salicylhydroxamic acid slightly inhibited, and their combination strongly inhibited respiration, as did 10 millimolar NaN(3). Tricarboxylic acid cycle members and ascorbate were more effective substrates than sugars, but acetate and glutarate strongly inhibited.Disc respiration showed the same early peak as whole fruit respiration; this peak is thus an inherent characteristic of postharvest development and cannot be ascribed to differences between ovaries of the aggregatetype fruit. The capacity of the respiratory apparatus did not change during this preclimacteric peak, but the contents of rate-limiting malate and citrate increased after harvest.It is concluded that the preclimacteric rise in CO(2) evolution reflects increased mitochondrial respiration because of enhanced supply of carboxylates as a substrate, probably induced by detachment from the tree. The second rise corresponds with the respiration during ripening of other climacteric fruits.

Journal Article↗
PubMed1989

Specificity of aspartate aminotransferases from leguminous plants for 4-substituted glutamic acids.

Aspartate aminotransferase (glutamate-oxalacetate transaminase) was partially purified from extracts of germinating seeds of peanut (Arachis hypogaea), honey locust (Gleditsia triacanthos), soybean (Glycine max), and Sophora japonica. The ability of these enzyme preparations, as well as aspartate aminotransferase purified from pig heart cytosol, to use 4-substituted glutamic acids as amino group donors and their corresponding 2-oxo acids as amino group acceptors in the aminotransferase reaction was measured. All 4-substituted glutamic acid analogs tested were poorer substrates than was glutamate or 2-oxoglutarate. 2-Oxo-4-methyleneglutarate was least effective (lowest relative V(m)/K(m)) as a substrate for the enzyme from peanuts and honey locust, which are the two species studied that accumulate 4-methyleneglutamic acid and 4-methyleneglutamine. Of the different aminotransferases tested, the enzyme from honey locust was the least active with 2-oxo-4-hydroxy-4-methylglutarate, the corresponding amino acid of which also accumulates in that species. These results suggest that transamination of 2-oxo-4-substituted glutaric acids is not involved in the biosynthesis of the corresponding 4-substituted glutamic acids in these species. Rather, accumulation of certain 4-substituted glutamic acids in these instances may be, in part, the result of the inefficacy of their transamination by aspartate aminotransferase.

Journal Article↗
PubMed2006

Poly[(mu2-1,3-di-4-pyridylpropane-kappa2N:N')(mu3-glutarato-kappa3O:O':O'')dizinc(II)].

The title compound, [Zn2(C5H6O4)2(C13H14N2)]n or [Zn2(glu)2(bpp)]n, is a novel zinc polymer based on mixed flexible glutarate (glu) and 1,3-di-4-pyridylpropane (bpp) ligands. The Zn(II) center has a distorted tetrahedral geometry and the central atom of the bpp ligand is located at a special site with a C2 axis passing through it. A layer is formed by Zn-glu bonding. Such layers are pillared by bpp ligands, forming a three-dimensional framework with large channels. The inverted interpenetration of two three-dimensional frameworks completes the molecular structure.

Journal Article↗
PubMed2005

X-ray studies on crystalline complexes involving amino acids and peptides. XLII. Adipic acid complexes of L- and DL-arginine and supramolecular association in arginine-dicarboxylic acid complexes.

The adipic acid complexes of DL-arginine and L-arginine are made up of zwitterionic, singularly positively charged arginium ions and doubly negatively charged adipate ions, with a 2:1 stoichiometry. One of the two crystallographically independent arginium ions in the L-arginine complex has a conformation hitherto unobserved in crystal structures containing the amino acid. In the present study the structural data on arginine complexes of saturated dicarboxylic acids with 0-5 C atoms separating the two carboxyl functions are given. In terms of molecular aggregation, formic and acetic acid complexes behave in a similar way to those involving fairly long carboxylic acids such as adipic acid. By and large, the supramolecular assembly in complexes involving dicarboxylic acids with 3 or more C atoms separating the carboxyl groups (glutaric, adipic and pimelic acids), and those involving formic and acetic acids, have common features. The aggregation patterns in complexes involving oxalic, malonic and maleic acids do not share striking features among themselves (except for the mode of hydrogen-bonded dimerization of arginium ions) or with those involving larger dicarboxylic acids. Complexes of succinic acid, the shortest linear dicarboxylic acid, share features with those involving shorter as well as longer dicarboxylic acids. The difference in the behaviour of long and short dicarboxylic acids and the ambiguous behaviour of succinic acid can be broadly related to their lengths.

Adipates↗
PubMed1999

Characterization of a soluble ternary complex formed between human interferon-beta-1a and its receptor chains.

The extracellular portions of the chains that comprise the human type I interferon receptor, IFNAR1 and IFNAR2, have been expressed and purified as recombinant soluble His-tagged proteins, and their interactions with each other and with human interferon-beta-1a (IFN-beta-1a) were studied by gel filtration and by cross-linking. By gel filtration, no stable binary complexes between IFN-beta-1a and IFNAR1, or between IFNAR1 and IFNAR2 were detected. However, a stable binary complex formed between IFN-beta-1a and IFNAR2. Analysis of binary complex formation using various molar excesses of IFN-beta-1a and IFNAR2 indicated that the complex had a 1:1 stoichiometry, and reducing SDS-PAGE of the binary complex treated with the cross-linking reagent dissucinimidyl glutarate (DSG) indicated that the major cross-linked species had an apparent Mr consistent with the sum of its two individual components. Gel filtration of a mixture of IFNAR1 and the IFN-beta-1a/IFNAR2 complex indicated that the three proteins formed a stable ternary complex. Analysis of ternary complex formation using various molar excesses of IFNAR1 and the IFN-beta-1a/IFNAR2 complex indicated that the ternary complex had a 1:1:1 stoichiometry, and reducing SDS-PAGE of the ternary complex treated with DSG indicated that the major cross-linked species had an apparent Mr consistent with the sum of its three individual components. We conclude that the ternary complex forms by the sequential association of IFN-beta-1a with IFNAR2, followed by the association of IFNAR1 with the preformed binary complex. The ability to produce the IFN-beta-1a/IFNAR2 and IFN-beta-1a/IFNAR1/IFNAR2 complexes make them attractive candidates for X-ray crystallography studies aimed at determining the molecular interactions between IFN-beta-1a and its receptor.

Chromatography, Gel↗
PubMed1976

Blood leucocyte enzymes. III. Diurnal rhythm of activity in isolated lymphocytes of normal subjects and chronic lymphatic leukaemia patients.

The activities of glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP oxidoreductase, G6PD), 6 phosphate glucono dehydrogenase (6 phospho-D-gluconate: NADP oxidoreductase, 6PGD) lactate dehydrogenase (D-lactate: NAD oxidoreductase, LDH), glutamate oxaloacetate transaminase (L-aspartate: 2-oxo-glutarate aminotransferase, GOT) and hexokinase (ATP: D-hexo-6-phosphotrans-ferase, Hx) were measured over 24 h in isolated lymphocytes of normal subjects and in white cells of patients with chronic lymphatic leukaemia (CLL). The activitty patterns of all enzymes in the normal lymphocytes were similar. A computed pattern of all the results exhibited a circadian rhythm of activity with the highest level at 16.00 hours. The oscillations in the activities of the same enzymes in the CLL cells differed among the patients, although all the enzymes of the same individual showed a similar diurnal rhythmic pattern. All peaks in this group appeared between 20.00 and 08.00 hours. The possible importance of these observations in setting up therapeutic schedules was raised.

Aspartate Aminotransferases↗
PubMed1975

Hydrogen exchane at the beta-carbon of amino acids during transamination.

The hydrogen exchange at the Beta-carbon of L-alanine, L-glutamate and L-asparate with water has been examined during transamination catalyzed by glutamic-oxaloacetic transaminase and by glutamic-pyruvic transaminase. A significant hydrogen exchange at the Beta-carbon has been demonstrated during incubation of L-[3-3H]alanine + glutamic-pyruvic transaminase, L-[3-3H]alanine + alpha-oxo-glutarate + glutamic-pyruvic transaminase, L-[3-3H]glutamate + glutamic-oxaloacetic transaminase, L-[3-3H]glutamate + oxaloacetate +glutamic-oxaloacetic transaminase, and L-[3-3H]glutamate + pyruvate + glutamic-pyruvic transaminase as shown by the appearance of 3H2O. No hydrogen exchange at the Beta-carbon of L-glutamate occurred during incubation of L-[3-3H]-glutamate with glutamic-pyruvic transaminase alone. The hydrogen exchaned at the Beta-carbon of L-glutamate coincides with transamination as demonstrated by nuclear magnetic resonance studies of 2H2O-L-glutamate exchange during transamination by glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase. No hydrogen exchange at the Beta-carbon occurred during transamination of L-aspartate by glutamic-oxaloacetic transaminase as shown by nuclear magnetic resonance spectroscopy and confirmed by nuclear magnetic resonance simulation studies. The results are discussed with special reference to the different equilibria between the pyridoxal form and the pyridoxamine form of glutamic-oxaloacetic transaminase and of glutamic-pyruvic transaminase.

Alanine Transaminase↗
PubMed1978

The reaction of pyruvate with saccharopine dehydrogenase.

The preceding paper in this journal has reported that pyruvate could be substituted for 2-oxo-glutarate as a substrate of saccharopine dehydrogenase [epsilon-N-(L-glutaryl-2)-L-lysine:NAD oxidoreductase (L-lysine-forming) in the direction of reductive condensation. In the present communication, the kinetic mechanism of saccharopine dehydrogenase reaction with NADH, L-lysine and pyruvate as reactants is reported. The results of initial velocity study, inhibition studies with lysine analogs and a reaction product, NAD+, are consistent with an ordered mechanism with the coenzyme binding first and pyruvate last. The reaction mechanism is at variance with that of the normal reaction in which 2-oxoglutarate is the substrate, in that the order of addition of the amino and oxo acid substrates is reversed. This fact suggests that there exists a small degree of randomness in the binding of amino and oxo acid substrates. From a product inhibition study, NAD+ was shown to be the last reactant released. Saccharopine [epsilon-N-(L-glutaryl-2)-L-lysine] was found to act as a potent dead-end inhibitor of the condensation reactions (of lysine and 2-oxoglutarate, and of lysine and pyruvate) by forming an abortive E. NADH. saccharopine complex.

Kinetics↗
PubMed1982

New mutants resistant to glucose repression affected in the regulation of the NADH reoxidation.

Spontaneous mutants resistant to vanadate, arsenate or thiophosphate were isolated from a haploid strain of Saccharomyces cerevisiae. These three anions have an inhibitory effect on some mitochondrial functions and at the level of glyceraldehyde 3-phosphate dehydrogenase, a glycolysis enzyme. All the selected mutants had the same phenotype: they were deficient in alcohol dehydrogenase I, the terminal enzyme of the glycolysis, and possessed a high content of cytochrome c oxidase, the terminal enzyme of the respiratory chain. Moreover, cytochrome c oxidase biosynthesis had become insensitive to the catabolite repression, while the biosynthesis of the other enzymes sensitive to this phenomenon were always inhibited by glucose. Metabolic effects of this pleiotropic mutation manifested themselves in the following ways. 1. Growth rate and final cell mass were enhanced, compared to the wild type, when cells were grown on glucose or on glycerol, but not on lactate or ethanol. 2. Growth under anaerobiosis was nil and mutants did not ferment. 3. Mitochondrial respiration of the mutant strains was identical to the wild type with succinate or 2-oxo-glutarate as substrate, and weak with ethanol. But with added NADH, respiration rate of the mutants was higher than that of the wild type and partially insensitive to antimycin, even when cells were grown in repression conditions. It is postulated that in mutants strains, NADH produced at the level of glyceraldehyde 3-phosphate dehydrogenase, failing to be reoxidized via alcohol dehydrogenase, could be reoxidized with a high turnover owing to the enhancement of the amount of cytochrome c oxidase. Since NADH reoxidation is partially insensitive to antimycin, a secondary pathway going from external NADH dehydrogenase to cytochrome c oxidase is suggested.

Alcohol Oxidoreductases↗
PubMed1986

Purification and characterization of (2S)-flavanone 3-hydroxylase from Petunia hybrida.

(2S)-Flavanone 3-hydroxylase from flowers of Petunia hybrida catalyses the conversion of (2S)-naringenin to (2R,3R)-dihydrokaempferol. The enzyme could be partially stabilized under anaerobic conditions in the presence of ascorbate. For purification, 2-oxoglutarate and Fe2+ had to be added to the buffers. The hydroxylase was purified about 200-fold by a six-step procedure with low recovery. The Mr of the enzyme was estimated by gel filtration to be about 74,000. The hydroxylase reaction has a pH optimum at pH 8.5 and requires as cofactors oxygen, 2-oxoglutarate, Fe2+ and ascorbate. With 2-oxo[1-14C]glutarate in the enzyme assay dihydrokaempferol and 14CO2 are formed in a molar ratio of 1:1. Catalase stimulates the reaction. The product was unequivocally identified as (+)-(2R,3R)-dihydrokaempferol. (2S)-Naringenin, but not the (2R)-enantiomer is a substrate of the hydroxylase. (2S)-Eriodictyol is converted to (2R,3R)-dihydroquercetin. In contrast, 5,7,3',4',5'-pentahydroxy-flavanone is not a substrate. Apparent Michaelis constants for (2S)-naringenin and 2-oxoglutarate were determined to be respectively 5.6 mumol X l-1 and 20 mumol X l-1 at pH 8.5. The Km for (2S)-eriodictyol is 12 mumol X l-1 at pH 8.0. Pyridine 2,4-dicarboxylate and 2,5-dicarboxylate are strong competitive inhibitors with respect to 2-oxoglutarate with Ki values of 1.2 mumol X l-1 and 40 mumol X l-1, respectively.

Catalase↗
PubMed1990

Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme.

1. 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (EC 4.1.3.5) in extracts of rat liver mitochondria can be inactivated by succinyl-CoA and activated by incubation in a medium designed to cause desuccinylation ('desuccinylation medium'). 2. The enzyme is less active in extracts of whole liver from control rats than from rats treated with glucagon or mannoheptulose. Incubation in desuccinylation medium raises the activity in extracts from control rats to the same value as treated rats, suggesting that the extent of succinylation in vivo is greater in controls than in hormone-treated animals. 3. This result is also obtained in liver homogenates and in isolated mitochondria. 4. Increasing the succinyl-CoA content of mitochondria to the same high level lowers the enzyme activity to the same value in mitochondria isolated from control or treated rats. In each case subsequent incubation of the lysates in desuccinylation medium raises the enzyme activity by the same extent. 5. Measurement of the incorporation of radiolabel from 2-oxo[5-14C]glutarate into protein is consistent with the proposal that all these changes in activity in isolated mitochondria may be explained by changes in the extent of succinylation of the enzyme. 6. From these data and our earlier work we conclude that, in vivo, mitochondrial HMG-CoA synthase in fed rats is normally substantially succinylated (about 40%) and inactivated, and that glucagon increases the activity of HMG-CoA synthase by lowering the concentration of succinyl-CoA and thus decreasing the extent of succinylation of the enzyme (to less than 10%). This may be an important control mechanism in ketogenesis.

Acyl Coenzyme A↗
PubMed1992

GC/MS analysis of urine in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

A patient with 3-hydroxy-3-methylglutaric aciduria was diagnosed using gas chromatography mass spectrometry. The patient had severe metabolic acidosis, hypoglycemia and hyperammonemia and excreted abnormal amounts of 3-methylglutaconic, 3-hydroxy-3-methylglutaric, 3-methylglutaric, 3-hydroxyisovaleric and glutaric acids in the urine. 3-Hydroxy-3-methylglutaric acid appeared as two peaks on the chromatogram after trimethylsilylation. One was a tri-trimethylsilyl and the other a di-trimethylsilyl derivative. 3-Methylglutaconic acid appeared as three peaks: cis-, trans- and cyclic cis-isomers. The structure of these derivatives was elucidated by deuterium-labeled trimethylsilyl derivatization. The di-trimethylsilyl derivative of 3-hydroxy-3-methylglutaric acid and the cyclic cis-isomer of 3-methylglutaconic acid do not appear to have been previously described. After treatment with leucine restriction milk, the excretion of leucine catabolites decreased but 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids continued to be excreted at abnormally high levels. It is concluded that these two metabolites are necessary for the chemical diagnosis of HMG-CoA lyase deficiency. This patient is the first case of HMG-CoA lyase deficiency to be reported in Japan.

Acidosis↗
PubMedDate not supplied

Involvement of protein phosphatases in differential regulation of renal proximal tubular PAH and sodium-dependent dicarboxylate transport.

It has been demonstrated that the basolateral organic allion (PAH) transporter and the sodium-dependent dicarboxylate transporter of rabbit renal proximal tubules are regulated differentially. A variety of protein kinases has been shown to be involved in the regulation of organic anion transport while dicarboxylate uptake, to which the first is coupled functionally, is not influenced by these kinases. This study was undertaken to elucidate whether respective transporter activities are modulated differentially by protein phosphatases as well. The experiments were performed on isolated S, segments of proximal tubules microdissected from rabbit kidneys without the use of enzymatic agents. 3H-PAH was used as marker substance of the PAH transporter, 14C-glutarate as a marker of the sodium dicarboxylate cotransporter. 30 s tubular uptake measurements were performed. Vanadate (10(-3) M), a selective inhibitor of tyrosine phosphatase, did not reduce PAH uptake significantly, while inhibitors of the serine threonine phosphatases 1 and 2A, okadaic acid and calyculin A (10(-6) M, each) induced a significant decrease of 30 s PAH uptake (by 32.3% +/- 7.9% and 25.6% +/- 6.4%) but not a change in dicarboxylatc transport. These findings indicate that, in addition to a variety of protein kinases, serine threonine phosphatases have a role in the regulation of renal basolateral PAH transport. There is no effect of these phosphatases on basolateral 30s gutaltarate transport. Thus, additional evidence for differential regulation of short-time activiity of the transporters for PAH and dicarboxylates is provided.

Animals↗
PubMedDate not supplied

Alterations in the renal excretion of valproate and its metabolites after chronic treatment.

Urinary excretion of valproate (VPA, administered as its sodium salt) and its various metabolites was studied in rats before and after 6 weeks of chronic treatment with intraperitoneal (i.p.) injection of 200 mg/kg VPA three times daily. Urinary excretion was determined after i.p. injection of a single dose of 200 mg/kg VPA, to which [14C]labeled VPA had been added to yield a dose of 1 microCi/kg body weight. Unlabeled VPA and metabolites were determined in urine by gas chromatography-mass spectrometry (GC-MS). After injection of a single dose of VPA before onset of chronic treatment, approximately 40-50% of the dose administered was excreted in the urine within 24 h, mainly in the form of conjugated VPA and omega-oxidation products, i.e., 5-hydroxy-VPA and 2-propyl-glutaric acid. After chronic treatment, urinary excretion of total radioactivity increased approximately 75% as compared with activity before chronic treatment, demonstrating a marked increase in elimination rate of VPA during prolonged administration. Determination of VPA and metabolites in urine by GC-MS indicated that this enhanced elimination resulted mainly from increases in glucuronidation and beta-oxidation of VPA, whereas omega-oxidation was apparently not altered or was even reduced. The data strongly indicate that at least in rats VPA produces induction of its own metabolism during prolonged treatment.

Animals↗
PubMedDate not supplied

Mitochondrial respiration after cardiac perfusion with ethanol or acetaldehyde.

Hemodynamics, energetics, and mechanics of isolated working rat hearts were studied during perfusion with Krebs-Henseleit medium containing either ethanol (24 +/- 2 mM) or acetaldehyde (74 +/- 6 microM). After 60-min perfusion with agent, mitochondria were isolated from the hearts and assayed polarographically using glutamate, alpha-keto-glutarate, pyruvate-malate, and succinate-rotenone substrates. Hemodynamic and mechanical function of the ethanol-treated hearts declined significantly more than that of control hearts during the 60-min perfusion. The acetaldehyde-perfused hearts did not differ from the controls. A 90-sec washout period reversed the ethanol-induced depression of physiologic function. Respiratory function (respiratory control ratio and Qo2) of mitochondria isolated from the ethanol- and acetaldehyde-treated hearts was slightly, though not significantly, depressed compared with control hearts. These data indicate that ethanol and acetaldehyde, at physiologically significant concentrations, have dissimilar effects on cardiac hemodynamics and mechanics: ethanol has a direct depressive effect which is reversible; acetaldehyde has no significant effect. Mitochondrial respiration is not irreversibly affected by brief exposure to ethanol or acetaldehyde at the concentrations tested.

Acetaldehyde↗