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PubMedDate not supplied

Breast feeding in organic acidaemias.

Breast feeding has been recommended for the dietary treatment of infants with organic acidaemias, but studies documenting clinical experience are still very few. Nine infants, diagnosed with methylmalonic acidaemia (n = 4), propionic acidaemia (n = 1), isovaleric acidaemia (n = 2) and glutaric acidaemia type I (n = 2) were breast fed after diagnosis. The age of the patients was 28.9+/- 13.4 months (mean +/- SD) (range 10-57 months). Eight patients were diagnosed with clinical symptoms and one because of an affected sibling. After the control of acute metabolic problems, an initial period with a measured volume of expressed breast milk was continued with on-demand breast feeding with the addition of a special essential amino acid mixture and energy supplements. Breast feeding was well tolerated in seven infants with good growth, metabolic control and neurological outcome. The duration of breast feeding was 12.3+/- 7.4 months (mean +/- SD) (range 4-24 months) in these patients. Breast feeding was terminated in the patient with propionic acidaemia because of two acute metabolic episodes requiring hospitalization, and could not be continued in one of the patients with isovaleric acidaemia owing to shortage of breast milk. A decrease in the frequency of infections, acute metabolic episodes and hospital admissions was observed in breast-fed infants. Breast feeding of infants with organic acidaemias is feasible with close monitoring of clinical parameters such as growth, development and biochemistry, including amino acids, organic acids and ammonia.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Promotion of oxidative stress by 3-hydroxyglutaric acid in rat striatum.

The pathophysiology of the striatum degeneration characteristic of patients affected by the inherited neurometabolic disorder glutaryl-CoA dehydrogenase deficiency (GDD), also known as glutaric aciduria type I, is still in debate. We have previously reported that 3-hydroxyglutaric acid (3-OH-GA) considered the main neurotoxin in this disorder, induces oxidative stress in rat cerebral cotex. In the present work, we extended these studies by investigating the in vitro effect of 3-OH-GA, at concentrations ranging from 0.01 to 1.0 mmol/L on the brain antioxidant defences by measuring total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and glutathione (GSH) levels, and on the production of hydrogen peroxide (H(2)O(2)), nitric oxide (NO) and malondialdehyde in striatum homogenates from young rats. We observed that TRAP, TAR and GSH levels were markedly reduced (by up to 50%) when striatum homogenates were treated with 3-OH-GA. In contrast, H(2)O(2) (up to 44%), NO (up to 95%) and malondialdehyde levels (up to 28%) were significantly increased by 3-OH-GA. These data indicate that total nonenzymatic antioxidant defences (TRAP) and the tissue capacity to handle an increase of reactive species (TAR) were reduced by 3-OH-GA in the striatum. Furthermore, the results also reflect an increase of lipid peroxidation, probably secondary to 3-OH-GA-induced free radical production. Thus, it may be presumed that oxidative stress is involved in the neuropathology in GDD.

Animals↗
PubMed1978

Organic acid excretion in a patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency: facts and artefacts.

The organic acid excretion in a patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency is described. In addition to 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids, substantial amounts of glutaric and adipic acids were repeatedly observed. 3-Methylcrotonic acid and possibly one of its isomers was found to be formed artificially from 3-methylglutaconic acid.

Acyl Coenzyme A↗
PubMed1977

A factor in yogurt which lowers cholesteremia in man.

Large dietary intakes of yogurt are found to lower cholestermia in man. This effect is associated with a reduction of incorporation of radioacetate into serum cholesterol. The effect appears slowly and persists after intake of the yogurt stops suggesting that the mechanism involves the synthesis of a regulatory protein rather than an allosteric effect. The effective agent is postulated to be hydroxymethyl glutarate which inhibits the regulatory enzyme hydroxymethyl glutaryl CoA reductase (EC 1.1.1.3.4).

Adult↗
PubMed1991

Deposition of dibasic esters in the upper respiratory tract of the male and female Sprague-Dawley rat.

Inhalation exposure of the male and female rat to high concentrations of a mixture of the dibasic esters dimethyl succinate (DMS), dimethyl glutarate (DMG), and dimethyl adipate (DMA) results in mild olfactory toxicity. This response is thought to be due to the in situ formation of acidic metabolites via nasal carboxylesterases. The current study was designed to provide inhalation dosimetric information for these vapors. Deposition of DMS, DMG, and DMA was measured in the surgically isolated upper respiratory tracts (URT) of ketamine-xylazine-anesthetized male and female rats under constant velocity flow conditions at a flow rate of 100 ml/min. Deposition of acetone was measured in both genders for comparative purposes. URT deposition efficiencies in excess of 98.3% were observed for DMS, DMG, and DMA in animals exposed to each vapor individually. No gender differences in deposition efficiency were observed for these vapors or for acetone. Deposition of DMS, DMG, and DMA was also measured in animals exposed to all three vapors simultaneously. Deposition efficiency under simultaneous exposure conditions ranged between 97.3 and 98.5%. These values were slightly lower (about 1%) than those obtained under individual exposure conditions (p less than 0.0001). The reduced deposition efficiency may have resulted from competitive inhibition of nasal metabolism due to the simultaneous presence of all three carboxylesterase substrate vapors in nasal tissues. If so, inhalation of dibasic ester vapors would be expected to inhibit the uptake of other carboxylesterase substrate vapors without influencing uptake of vapors which are not substrates for this enzyme. Such was observed in studies using DMS, ethyl acetate (the substrate vapor), and isoamyl alcohol (the nonsubstrate vapor). Specifically, simultaneous exposure to DMS markedly inhibited uptake of ethyl acetate without altering uptake of isoamyl alcohol. Gender differences were not observed in URT deposition of any of the six vapors used in the current study, DMS, DMG, DMA, ethyl acetate, isoamyl alcohol, or acetone, suggesting that gender differences in URT deposition may not be widespread among vapors. The high URT deposition efficiencies of the dibasic esters are consistent with the olfactory toxicity resulting from inhalation exposure to these vapors.

Acetates↗
PubMed1991

Carboxylesterase-dependent cytotoxicity of dibasic esters (DBE) in rat nasal explants.

Dibasic esters (DBE) are a solvent mixture of dimethyl adipate (DMA), dimethyl glutarate (DMG), and dimethyl succinate (DMS) used in the paint and coating industry. Subchronic inhalation toxicity studies have demonstrated that DBE induce a mild degeneration of the olfactory, but not the respiratory, epithelium of the rat nasal cavity. Carboxylesterase-mediated hydrolysis of the individual dibasic esters is more efficient in olfactory than in respiratory mucosal homogenates. In the present study, an in vitro system of cultured rat nasal explants was utilized to determine if DBE toxicity is dependent on a metabolic activation by nonspecific carboxylesterase. Explants from both the olfactory and the respiratory regions of the female rat nasal cavity were incubated for 2 hr in Williams' medium E containing 10-100 mM DMA, DMG, or DMS. DBE caused a dose-related increase in nasal explant acid phosphatase release, a biochemical index of cytotoxicity. HPLC analysis demonstrated parallel increases in the carboxylesterase-mediated formation of monomethyl ester metabolites. Diacid metabolite production in the nasal explant system was not entirely concentration-dependent. Metabolite concentrations and acid phosphatase release were generally greater in olfactory than respiratory tissues. DBE-induced cytotoxicity and acid metabolite production were markedly attenuated in nasal tissue excised from rats which were pretreated with bis(p-nitrophenyl)phosphate, a carboxylesterase inhibitor. This study presents a viable in vitro method for assessing organic ester cytotoxicity in the rat nasal cavity. It was shown that DBE are weak nasal toxicants under the conditions of this system. It was further demonstrated that DBE toxicity is dependent on a carboxylesterase-mediated activation. A similar mechanism was proposed for the nasal toxicity induced by other organic esters following inhalation exposure.

Acid Phosphatase↗
PubMed1990

Glucose increases spontaneous platelet aggregation in whole blood.

Glucose (10-50 mM) added to samples of citrated whole blood increased the spontaneous platelet aggregation (SPA) that was observed upon stirring the samples, in a dose-dependent but time-independent manner. EDTA prevented and also reversed the SPA that occurred in the presence of glucose. Galactose, fructose and 2-deoxyglucose, but not sorbitol and sucrose, had effects on SPA similar to those of glucose. The effect of glucose on SPA in whole blood could not be specifically inhibited by tetramethylene glutaric acid (an inhibitor of aldose reductase). SPA was not affected by pentoxifylline, but was markedly reduced by chlorpromazine. We previously found that glucose, galactose, fructose and 2-deoxyglucose, but not sorbitol and sucrose, render red blood cells more fragile, and the results obtained in the present study provide further evidence that glucose as well as other reducing sugars potentiate SPA in whole blood by liberating ADP or other aggregating material from red blood cells.

Carbohydrates↗
PubMedDate not supplied

The evaluation of genotoxic activities of disinfectants and their metabolites by umu test.

The genotoxic potential of 6 disinfectants and their 9 metabolites was investigated by umu test. In the tested disinfectants, glutaraldehyde showed positive genotoxicity independent of metabolic activation system and acrinol was positive only in the presence of S9 mixture. Alkylaminoethylglycine, benzalkonium chloride, chlorhexidine digluconate and methylrosaniline chloride were negative in the presence or absence of S9 mixture. In some metabolites of benzalkonium chloride, chlorhexidine digluconate or glutaraldehyde, only pyrogallol showed positive genotoxicity in the absence of S9 mixture and the activity was not affected by the metabolic activation system. Aniline, p-chloroacetoanilide, p-chloroaniline, p-chlorophenol, decabutyldimethylamine, glutaric acid, phenol and pyrocatechol did not induce umu gene expression independently of the presence of S9 mixture. The results in the umu test of these compounds were compared with their findings in the liquid rec-assay and Ames test. The umu test is a more useful and simplified method for the detection of genotoxicity of the compounds with killing effects on tester bacteria.

Benzalkonium Compounds↗
PubMed2005

Functional expression of pig renal organic anion transporter 3 (pOAT3).

With the cloning of pig renal organic anion transporter 1 (pOAT1) (Biochimie 84 (2002) 1219) we set up a model system for comparative studies of cloned and natively isolated membrane located transport proteins. Meanwhile, another transport protein involved in p-aminohippurate (PAH) uptake on the basolateral side of the proximal tubule cells was identified, designated organic anion transporter 3 (OAT3). To explore the contribution of pOAT1 to the PAH clearance in comparison to OAT3, it was the aim of this study to extend our model by cloning of the pig ortholog of OAT3. Sequence comparisons of human organic anion transporter 3 (hOAT3) with the expressed sequence tag (EST) database revealed a clone and partial sequence of the pig renal organic anion transporter 3 (pOAT3) ortholog. Sequencing of the entire open reading frame resulted in a protein of 543 amino acid residues encoded by 1632 base pairs (EMBL Acc. No. AJ587003). It showed high homologies of 81%, 80%, 76%, and 77% to the human, rabbit, rat, and mouse OAT3, respectively. A functional characterization of pOAT3 in Xenopus laevis oocytes yielded an apparent Km (Kt) for [3H]estrone sulfate of 7.8 +/- 1.3 microM. Moreover, pOAT3 mediated [3H]estrone sulfate uptake was almost abolished by 0.5 mM of glutarate, dehydroepiandosterone sulfate, or probenecid consistent with the hallmarks of OAT3 function.

Amino Acid Sequence↗
PubMed2005

Encapsulation of chondrocytes in injectable alkali-treated collagen gels prepared using poly(ethylene glycol)-based 4-armed star polymer.

An in situ gel system was developed to encapsulate chondrocytes under physiological conditions using an alkali-treated collagen (AlCol) and pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate (4S-PEG) as a crosslinker. AlCol gels were obtained at crosslinker concentrations from 0.1 to 3.0 mM. Chondrocytes were encapsulated and dispersed homogeneously in AlCol gels. Results of MTT staining showed that cells survived after encapsulation in AlCol gels. Biochemical analysis demonstrated that DNA content in AlCol gels was constant after 3 weeks. Glycosaminoglycan content and mRNA expression of type II collagen and aggrecan increased with culture time. These results suggest that this in situ gel system is useful for regenerating cartilage in vitro and for minimally invasive therapy for cartilage defects.

Alkalies↗
PubMed2006

Physical stability enhancement of theophylline via cocrystallization.

The crystal form adopted by the respiratory drug theophylline was modified using a crystal engineering strategy in order to search for a solid material with improved physical stability. Cocrystals, also referred to as crystalline molecular complexes, were prepared with theophylline and one of several dicarboxylic acids. Four cocrystals of theophylline are reported, one each with oxalic, malonic, maleic and glutaric acids. Crystal structures were obtained for each cocrystal material, allowing an examination of the hydrogen bonding and crystal packing features. The cocrystal design scheme was partly based upon a series of recently reported cocrystals of the molecular analogue, caffeine, and comparisons in packing features are drawn between the two cocrystal series. The theophylline cocrystals were subjected to relative humidity challenges in order to assess their stability in relation to crystalline theophylline anhydrate and the equivalent caffeine cocrystals. None of the cocrystals in this study converted into a hydrated cocrystal upon storage at high relative humidity. Furthermore, the theophylline:oxalic acid cocrystal demonstrated superior humidity stability to theophylline anhydrate under the conditions examined, while the other cocrystals appeared to offer comparable stability to that of theophylline anhydrate. The results demonstrate the feasibility of pharmaceutical cocrystal design based upon the crystallization preferences of a molecular analogue, and furthermore show that avoidance of hydrate formation and improvement in physical stability is possible via pharmaceutical cocrystallization.

Bronchodilator Agents↗
PubMed2004

Evidence that 3-hydroxyglutaric acid interacts with NMDA receptors in synaptic plasma membranes from cerebral cortex of young rats.

Neurological symptoms are common in patients with glutaric acidemia type I (GA-I). Although the pathophysiology of this disorder is not yet fully established, 3-hydroxyglutaric acid (3-HGA), which accumulates in affected patients, has recently been demonstrated to be excitotoxic to embryonic chick and neonatal rat neurons probably via NMDA glutamate receptors. In the present study, we investigated the in vitro effects of 3-HGA on the [(3)H]glutamate and [(3)H]MK-801 (dizocilpine) binding to rat synaptic plasma membranes from cerebral cortex of young rats in order to elucidate the interactions of 3-HGA with glutamate receptors and its possible contribution to the in vitro excitotoxic properties of 3-HGA. 3-HGA (10-100 microM) significantly decreased Na(+)-dependent (up to 62%) and Na(+)-independent (up to 30%) [(3)H]glutamate binding to synaptic membranes, reflecting a possible competition between glutamate and 3-HGA for the glutamate transporter and receptor sites, respectively. Since a decrease in Na(+)-independent glutamate binding might represent an interaction of 3-HGA with glutamate receptors, we next investigated whether 3-HGA interacts with NMDA receptors by adding NMDA alone or combined with 3-HGA and measuring Na(+)-independent [(3)H]glutamate binding to synaptic membranes (binding to receptors). We verified that 3-HGA and NMDA, at 10 and 100 microM concentrations, decreased glutamate binding by up to 20 and 45%, respectively, and that the simultaneous addition of both substances did not provoke an additive effect, implying that they bind to NMDA receptors at the same site. Furthermore, the binding of the NMDA-channel blocker [(3)H ]MK-801 was significantly increased (approximately 32-40%) by 10 and 100 microM 3-HGA, implying that 3-HGA was able to open the NMDA channel allowing MK-801 binding, which is a characteristic of NMDA agonists. On the other hand, glutamate had a much higher stimulatory effect on this binding (180% increase), reflecting its strong NMDA agonist property. Furthermore, the simultaneous addition of 3-HGA and glutamate provoked an additive stimulatory effect on [(3)H]MK-801 binding to the NMDA receptor. These data indicate that, relatively to glutamate, 3-HGA is a weak agonist of NMDA receptors. Finally, we demonstrated that 3-HGA provoked a significant increase of extracellular calcium uptake by cerebral cortex slices, strengthening therefore, the view that 3-HGA activates NMDA receptors. The present study therefore, demonstrates at the molecular level that 3-HGA modulates glutamatergic neurotransmission and may explain previous findings relating the neurotoxic actions of this organic acid with excitotoxicity.

Animals↗
PubMed2005

Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.

Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The urine organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of urine organic acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.

Adult↗
PubMed2002

3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defenses in cerebral cortex of young rats.

Glutaryl-CoA dehydrogenase deficiency (GDD) is an inherited neurometabolic disorder biochemically characterized by tissue accumulation of glutaric, 3-hydroxyglutaric (3-OHGA) and glutaconic acids and clinically by severe neurological symptoms and cerebral atrophy whose pathophysiology is poorly known. In the present study we investigated the effect of 3-OHGA, considered the main neurotoxin in GDD, on the lipoperoxidation parameters chemiluminescence and thiobarbituric acid-reactive species (TBA-RS), and on the amount of nitric oxide metabolites in cerebral cortex of young rats. Total radical-trapping antioxidant potential (TRAP), which reflects the tissue antioxidant defenses, was also examined. We observed that 3-OHGA significantly increased chemiluminescence, TBA-RS and nitric oxide metabolites, in contrast to TRAP, which was decreased by the metabolite. The data indicate a stimulation of lipid peroxidation and free radical production, and a reduction of the tissue antioxidant defenses caused by the metabolite. In case these findings also occur in the human condition, it may be presumed that oxidative stress is involved in the brain damage observed in GDD.

Animals↗
PubMed1999

A GC/MS/MS screening method for multiple organic acidemias from urine specimens.

A gas chromatography tandem mass spectrometry method using an ion trap GC/MS system was developed to quickly screen urine samples for 14 organic acids associated with multiple organic acidemias. The following organic acids are used as diagnostic markers: methylmalonic acid, glutaric acid, 2-ketoisocaproic acid, succinylacetone, 3-methylcrotonylglycine, tiglylglycine, isovalerylglycine, fumaric acid, butyrylglycine, propionylglycine, hexanoylglycine, adipic acid, suberic acid, and sebacic acid. 2-ketocaproic acid is used as an internal standard. The samples are prepared using a solid-phase extraction and converted to trimethylsilyl derivatives. The extraction efficiency for the 14 compounds is between 57 and 106%. A derivatized standard mixture of the 14 markers is run prior to the patient samples to determine the accurate absolute and relative retention times. The samples are then injected and the product ion spectra monitored. For data analysis, one characteristic product ion plot is extracted for each of the 14 marker compounds, and the presence of a peak with the expected retention time is determined. The areas of the product ion peaks are compared with the reference range determined from 30 normal controls. Ten samples of patients with known organic acidemias were measured. For all patients, diagnostic peaks at the expected retention times of at least five times the upper limit of the reference range were detected. The method, with its relatively fast sample preparation, short 10.0 min run time and simple data analysis, is suitable for use as a quick metabolic screen of very sick patients in whom there is concern regarding the possibility of a treatable inborn error.

Acids↗
PubMed1989

Advances in the use of computerized gas chromatography-mass spectrometry and high-performance liquid chromatography with rapid scanning detection for clinical diagnosis.

A multi-component analytical system designed for the diagnosis of metabolic disorders is described. The urinary components are separated by a variety of chromatographic techniques, including automated amino acid analysis, high-performance liquid chromatography with diode-array detection and gas chromatography-mass spectrometry with a computerized mass spectral library search for identification of organic acids. The complete system can be used to diagnose over 100 different metabolic diseases. The usefulness of the chromatographic system is exemplified by the pre- and postnatal diagnosis of glutaric aciduria type I, the diagnosis of lysinuric protein intolerance and of alkaptonuria. Drugs and diet may cause interfering metabolites, as exemplified by glycofurol, used as a solvent for intravenous drugs, and saccharin. It is predicted that chromatography and mass spectrometry will continue to be important diagnostic tools for many years ahead.

Acids↗
PubMed1998

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life.

OBJECTIVE: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1999

Hypoketotic hypoglycemic coma in a 21-month-old child.

We present the case of a 21-month-old child with hypoketotic hypoglycemic coma. The differential diagnosis initially included metabolic causes versus a toxicologic emergency (unripe ackee fruit poisoning). Using information obtained from the emergency department, the diagnosis was confirmed as the late-onset form of glutaric acidemia type II. This case illustrates the importance of emergency physicians in the diagnosis and management of children with inborn errors of metabolism.

Acidosis↗