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PubMed1995

Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency is an X-linked disorder of the urea cycle that can cause hyperammonemic encephalopathy in hemizygous males and heterozygous females. Affected females typically limit protein intake in their diet. This case report describes a 36-year-old woman with ulcerative colitis who went into hyperammonemic coma after administration of total parenteral nutrition. A similar episode of coma had occurred 7 years earlier after she delivered a normal boy. Heterozygous ornithine transcarbamylase deficiency was diagnosed based on a positive allopurinol tolerance test result after elevated levels of plasma glutamine and low plasma citrulline were detected. The protein load associated with parenteral alimentation resulted in symptomatic expression of this partial enzyme deficiency in this unique case. Partial ornithine transcarbamylase deficiency must always be considered in adult women and men with hyperammonemia who have normal liver function test results.

Adult↗
PubMed1989

Continuous intravenous ammonia infusion as a model for the study of hepatic encephalopathy in rabbits.

To obtain a more precise pathophysiological evaluation of the role of ammonia in acute hepatic encephalopathy, we compared the plasma ammonia concentrations and electroencephalographic recordings (EEGs) of rabbits with surgically induced acute hepatic failure (AHF, n = 10) and normal rabbits administered an infusion of ammonium acetate (NH4-Ac, n = 7) over a 10-hr period. AHF was surgically induced by portocaval shunting followed by hepatic artery ligation 48 hr later. In the infusion group the dose of NH4-Ac, initially 0.78 mmol/kg/hr, was increased every 2 hr by 0.13 mmole/kg/hr during a 10-hour period to simulate the arterial NH3 concentrations observed in AHF. Ammonia levels in rabbits administered the NH4-Ac infusion were identical to those observed in AHF, with the exception of the higher initial value in the AHF group. Moreover, the mean rates of increase in grade of encephalopathy in the two groups were similar, although the EEG grades in the infusion group were significantly less at all time points. In conclusion, this study demonstrates that a more pathophysiological approach to identification of the putative toxins in hepatic encephalopathy is feasible. Some of the EEG abnormalities of acute hepatic encephalopathy in rabbits are presumably due to hyperammonemia; the encephalopathy observed in AHF at zero time is probably caused by the previously constructed portocaval shunt via an undefined, but possibly also ammonia-related, mechanism.

Acetates↗
PubMed1995

Immunological abnormality in patients with lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a rare hereditary disorder manifesting hyperammonemia induced by low levels of basic amino acids, these low levels being due to the impaired transport of these acids in the intestinal mucosa and the renal tubules. Low serum arginine levels and probably the consequently low in vivo levels of nitric oxide (NO), which against acts as a physiological and immunological mediator/modulator, are thought to influence the immunological status in patients with LPI. Accordingly, this study was conducted to. We found that patients with LPI had leukocytopenia, high serum IgG levels, a high ratio of CD44B4-positive lymphocytes (helper inducer) to CD42H4-positive lymphocytes (suppressor inducer), low levels of leukocyte phagocytic, cytotoxic, and natural killer cell activity, and increased spontaneous proliferation of lymphocytes. These results were probably the consequence of persistent low NO levels in vivo.

Adult↗
PubMed1989

Brain cholecystokinin depletion in rats with acute liver failure.

A decrease of both hypothalamic and cortical CCK occurred in the brain of rats killed 8 hours after hepatic artery ligation following portocaval anastomosis. Brain CCK depletion was not reproduced by exogenously provoked hyperammonemia nor by insulin-induced hypoglycemia, thus suggesting a central mechanism for the derangement of the CCKergic system in the course of acute liver failure.

Ammonia↗
PubMed1991

Tumor-induced alterations in brain neurotransmitter and plasma ammonia concentrations are normalized twenty-four hours after tumor resection.

Tumor-induced anorexia was accompanied by significant elevations in plasma ammonia and lactate and by alteration of the plasma amino acid profile. The brains of anorectic tumor-bearing rats had increased levels of glutamine and most large neutral amino acids. Dopamine and serotonin metabolism were also increased in several brain regions of these rats. Resection of the tumor resulted in the normalization of most of these aberrations in blood and brain within 24 hrs. These results demonstrate a rapid reversal of tumor-induced biochemical alterations shortly after tumor removal and suggest that these aberrations may be secondary to hyperammonemia.

Amino Acids↗
PubMed1995

Effect of fermentable fructo-oligosaccharides on mineral, nitrogen and energy digestive balance in the rat.

In the present study, we have assessed the apparent retention of gross energy, nitrogen and Ca, Mg, Fe, Zn and Cu in rats receiving a diet supplemented with fermentable fructo-oligosaccharides with high and low degree of polymerization. Feeding 10% Raftilose (degree of polymerization: 4.8) or 10% Raftiline (degree of polymerization: 10) decreased to the same extent (a) the fecal excretion of all the minerals, despite an increase in total fecal mass excretion leading to an improvement of the absorption of Ca, Mg, Fe and Zn; (b) total gross energy absorption; and (c) led to an increase in the faecal excretion and to a decreased urinary excretion of nitrogen, suggesting a displacement of part of nitrogen excretion towards the large intestine. Feeding fermentable fructo-oligosaccharides may thus constitute a good way to counteract syndromes resulting from hyperammonemia or disturbed Fe, Ca, Mg and Zn homeostasis.

Animals↗
PubMed1976

Muscle nitrogen metabolism in chronic hepatic insufficiency.

Whole blood arterio-venous (A-V) differences for ammonia (NH3) and amino acids were determined across the forearm in 14 patients with decompensated alcoholic cirrhosis and hyperammonemia. NH3 was extracted by the forearm in all patients; however, the fractional extraction of NH3 was significantly less in five individuals with gross muscle wasting (13.3% versus 25.3%). There was neither a significant uptake nor release of NH3 in normal control subjects. The arterial concentrations of 12 out of 20 amino acids were strikingly diminished in the patient group. In contrast to normal subjects, in whom the release of alanine exceeds that of glutamine, the A-V difference for glutamine in the patients was threefold greater than that for alanine. The A-V differences for all other amino acids were not significantly different from zero. The results suggest that (1) muscle plays an important role in disposing of NH3 in patients with hepatic insufficiency and (2) a major fraction of NH3 taken up by muscle is released as glutamine.

Adult↗
PubMed1989

Cerebral glutamine metabolism: study of modulatory effects of glutamine on gamma-aminobutyric acid-ergic neurotransmission.

Glutamine is one major precursor of gamma-aminobutyric acid (GABA) and glutamate, the most important inhibitory and excitatory neurotransmitters in the mammalian brain, respectively. Changes in cerebral glutamine concentrations occur in various metabolic encephalopathies including hyperammonemia and liver failure. As glutamine inhibits the specific binding of GABA to its postsynaptic receptor at physiologic concentrations, in this study the effects of glutamine on various components of the GABAA-benzodiazepine receptor complex were studied. Glutamine dose dependently inhibited the stimulation of flunitrazepam binding by GABA. This inhibition occurred already at concentrations of 10 mumol/L glutamine. Glutamine had no effects on basal or GABA-stimulated synaptoneurosomal chloride uptake. It is concluded that glutamine is not a modulator of the GABAA-benzodiazepine neurotransmitter system. Thus, changes of cerebral glutamine concentrations are unlikely to contribute to the activation of GABA-ergic neurotransmission in liver failure.

Animals↗
PubMed1989

Hepatic metabolic alterations in rats treated with low-dose endotoxin and aspirin: an animal model of Reye's syndrome.

The administration of a sublethal dose of endotoxin (LPS) followed one hour later by a low dose of aspirin (LPS + ASA) to fasted rats leads to biochemical perturbations similar to Reye's syndrome. In this study hepatic energy metabolism was assessed in freeze-clamped liver samples (12 hours posttreatment) obtained from (250 to 300 g Sprague-Dawley) rats. The administration of aspirin alone to fasted rats did not significantly alter the hepatic levels of adenine nucleotides, total ketones, or acyl-CoA thioesters as compared to controls. In contrast, in both LPS and LPS + ASA samples, there were declines in ATP/ADP ratio (P less than .005), total ketones (P less than .001) and acetyl CoA (P less than .005) compared to their respective controls. A striking alteration in acyl-CoA thioesters was observed in LPS + ASA-treated animals. Unlike control, aspirin, or LPS-treated animals, LPS + ASA-treated animals accumulated relatively large amounts of unusual CoA esters, including propionyl-CoA, (iso)butyryl-CoA, beta-methylcrotonyl-CoA, and isovaleryl-CoA, metabolites of the branch chain amino acid and odd-chain fatty acid oxidation pathways. The acyl-CoA profile is similar to that obtained in patients with Reye's syndrome. Like human patients with Reye's syndrome, these rats showed hyperammonemia, compromised fatty acid oxidation, and accumulation of branched chain amino acid oxidation metabolites. Accumulation of these intermediates with LPS + ASA is a possible mechanism for the potentiation of Reye's syndrome by aspirin. These findings provide biochemical evidence that sublethal doses of LPS + ASA administered to fasted rats produces an animal model of Reye's syndrome.

Acyl Coenzyme A↗
PubMed1990

Effects of sublethal concentrations of phosphamidon, methyl parathion, DDT, and lindane on tissue nitrogen metabolism in the penaeid prawn, Metapenaeus monoceros (Fabricius).

Changes in midgut gland, muscle, and gill tissue nitrogen metabolic profiles studied in a penaeid prawn, Metapenaeus monoceros, following its exposure to sublethal concentrations of phosphamidon, methyl parathion, DDT, and lindane. In all the pesticide-exposed prawn tissues, ammonia levels were significantly increased and a shift in the nitrogen metabolism toward the synthesis of urea and glutamine was observed. Inhibition of glutamate oxidation to ammonia and alpha-ketoglutarate by glutamate dehydrogenase suggest a mechanism whereby hyperammonemia is reduced by minimizing the addition of further ammonia to the existing elevated ammonia. Aspartate (AAT) and alanine (AlAT) aminotransferases demonstrated an increase in their activity levels, suggesting gluconeogenesis. Pesticide-induced stress also seems to induce ammoniagenesis, which is due to increased deamination of purines. Mechanisms to detoxify the ammonia by enhancing the synthesis of urea and glutamine were observed in the tissues.

Animals↗
PubMed1994

Changes in oxidative metabolism in selected tissues of the crab (Scylla serrata) in response to cadmium toxicity.

Changes in oxidative metabolism were studied in hepatopancreas, muscle, and hemolymph of the edible crab Scylla serrata, exposed to a sublethal concentration (2.5 ppm) of cadmium chloride. A significant decrease in glycogen, total carbohydrates, and pyruvate and an increase in lactate levels in hepatopancreas and muscle were observed. Hemolymph sugar levels were increased in experimental crabs. An increase in phosphorylase suggested increased glycogenolysis during cadmium toxicity. The decrease in lactate dehydrogenase activity and the increase in lactate content indicated reduced mobilization of pyruvate into the citric acid cycle. Krebs cycle enzymes such as succinate dehydrogenase and malate dehydrogenase were found to be decreased, suggesting impairment of mitochondrial oxidative metabolism as a consequence of cadmium toxicity. Glucose-6-phosphate dehydrogenase activity was increased, suggesting enhanced oxidation of glucose by the HMP pathway. Cytochrome-c oxidase and Mg2+ ATPase activity levels decreased, indicating impaired energy synthesis during cadmium stress. Acid and alkaline phosphatase activities increased, suggesting enhanced breakdown of phosphates to release energy in view of impaired ATPase system during cadmium exposure. A significant decrease in protein and free amino acid and an increase in ammonia, urea, and glutamine levels were observed in the tissues during exposure. An increase in protease, alanine aminotransaminase, and aspartate aminotransaminase suggested increased proteolysis and transamination of amino acids. The increase in glutamate dehydrogenase, AMP deaminase, and adenosine deaminase indicated increased ammonia production. The increased arginase and glutamine synthetase suggested the detoxification or mobilization of ammonia toward the production of urea and glutamine. These results suggest that cadmium affects oxidative metabolism and induces hyperammonemia, and crabs switch over their metabolic profiles toward compensatory mechanisms for the survivability in cadmium-polluted habitats.

Adenosine Deaminase↗
PubMed1993

The biochemistry and toxicology of benzoic acid metabolism and its relationship to the elimination of waste nitrogen.

Detoxification of sodium benzoate by elimination as a conjugate with glycine, a nonessential amino acid, provides a pathway for the disposal of waste nitrogen. Since 1979, sodium benzoate has been widely used in the therapeutic regimen to combat ammonia toxicity in patients born with genetic defects in the urea cycle. Although the clinical use of benzoate is associated with improved outcome, the search for biochemical evidence in support of the rationale for benzoate therapy has produced conflicting results. This review begins with an historical account leading to elucidation of the biochemistry of benzoate detoxification and early work indicating the potential utility of the pathway for elimination of waste nitrogen. An introduction to contemporary efforts at employing benzoate to treat hyperammonemia is followed by a detailed review of studies on benzoate metabolism and resultant toxic interactions with other major metabolic pathways. With this background, the several metabolic routes by which benzoate is thought to promote the disposal of waste nitrogen are then examined, followed by a consideration of alternative mechanisms by which benzoate might combat ammonia toxicity.

Ammonia↗
PubMed1981

Relative effects of hyperbaric oxygen on cations and catecholamine metabolism in rats: protection by lithium against seizures.

Analysis of lithium (Li+) in the brain and blood after intraperitoneal injection (i.p.) shows that initially its concentration is high in blood and negligible in the brain. Subsequently its concentration increases in the brain and disappears from the blood. Lithium itself affects neurological actions but the mechanisms remain obscure. It also modifies the toxic action of oxygen at high pressure (OHP), which causes convulsions, either suppressing or exacerbating it. These clearly separate effects correspond with the presence of Li+ in the blood (suppression) or in the brain (exacerbating). Determination of the effect of Li+ and OHP upon cations, catecholamines, ammonia, tyrosine hydroxylase, and monamine oxidase on brain and blood tissue showed that there was very little correspondence between changes in the cations either with Li+ or the toxic effects of OHP. On the other hand, OHP developed a sustained blood and brain hyperammonemia in rats which could be negatively modified by Li+ in the blood. The latter effect also corresponded with a prolongation of convulsive latency. Changes in brain catecholamines, tyrosine hydroxylase, monoamine oxidase and tyrosine were effected by Li+ and potentiated by OHP. These data suggest that Li+ and OHP mediate their effects relatively more through developing hyperammoneic states in both blood and brain than by altering cation concentrations in these tissues.

Ammonia↗
PubMed1991

Hyperammonemic alterations in the uptake and release of glutamate and aspartate by rat cerebellar preparations.

Release and uptake of neurotransmitter amino acids, glutamate and aspartate, were studied in the synaptosomes, astrocytes and in the perikarya of granule neurons isolated from the cerebella of normal and hyperammonemic rats. During acute hyperammonemia, depolarization-induced release of both the amino acids from the synaptosomes was elevated. The Vmax values of high-affinity uptake systems were elevated without alterations in the Km values for these two amino acids during acute hyperammonemic states. In the case of the low-affinity uptake system of these two amino acids, there was a decrease in the Km values without alterations in the Vmax values. These results are discussed in relation to the mechanism of ammonia toxicity.

Ammonia↗
PubMed1991

Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes.

Binding of glutamate and muscimol (an agonist for GABAA receptors) to their respective receptors has been studied in the cerebellum of normal and hyperammonemic rats. There was a decrease in both high- and low-affinity binding of glutamate in the cerebellum during hyperammonemia. Kinetic studies revealed that the decrease is due to a reduction in the number of binding sites, but not due to changes in the binding affinities. Further studies also revealed that the decrease was only in the N-methyl-D-aspartate (NMDA)-specific binding sites without any alterations in the binding to non-NMDA sites represented by kianic acid (KA)- and quisqualic acid (QQ)-sensitive receptor sites. These effects were also mimicked when the membrane preparations from the cerebellum of normal animals were incubated with ammonium acetate. Enhancement of muscimol binding was observed in animals injected with ammonium acetate. It is concluded that hyperammonemic states, even in the presence of a functional liver, are capable of altering amino acid neurotransmission and this might play an important role in cerebral dysfunction under these conditions.

Ammonia↗
PubMed1992

Hyperammonemic alterations in the metabolism of glutamate and aspartate in rat cerebellar astrocytes.

Pathophysiological concentrations of ammonia, both in vivo and in vitro, suppressed the production of 14CO2 from 14C-labelled glutamate and aspartate in astrocytes isolated from the rat cerebellum. Suppression of 14CO2 production with (aminooxy)acetic acid but not with glutamic acid diethyl ester indicated that transamination plays a major role in the oxidation of glutamate carbons. Activities of the enzymes, aspartate amino-transferase, alanine aminotransferase and glutaminase were decreased while those of glutamate dehydrogenase and glutamine synthetase were enhanced in the cerebellar astrocytes during hyperammonemic states. These results suggest an impairment of astrocytic glutamate metabolism during hyperammonemia.

Acetates↗
PubMed1985

Functional relationship of ammonia to DNA, RNA and protein in brain.

The functional significance of the production of ammonia during neuronal activity is not known, although a number of studies are available concerning the mechanism of of ammonia toxicity in brain. Hyperammonemia without behavioural change was induced in experimental rats by i.p. administration of either a single dose of ammonium acetate or 6 doses with an interval of 1 h during the day or one single dose daily for 7 days. No significant change was observed in the content of DNA, RNA and protein in cerebral cortex, cerebellum and brain stem following the administration of a single dose. There was a marked decreased in the content of DNA in all three brain regions after the administration of 6 hourly doses of ammonium acetate. Under these conditions the RNA was found to increase in all three brain regions. A decrease in the content of protein per gram wet weight was observed in cerebral cortex and brain stem while the change in cerebellum was found to be insignificant. However, the content of RNA and protein was found to show a very significant increase when expressed per microgram of DNA for each region under these conditions, indicating an increase in RNA and protein in the cells surviving the toxic damage caused by ammonia. A marked and significant increase in the content of RNA and protein was observed in all three brain regions following the administration of a single dose per day for 7 days. These results are discussed not only with respect to toxic damage to the glial cells by ammonia, but also with respect to the probable effect of ammonia liberated during neuronal activity on inhibition of lysosomal degradation of protein, and on its stimulatory effects of transcriptional and translational activities. The increased RNA and protein under these conditions may be contributing not only in the proliferation of glial cells (Alzheimer Type II cells) but also in the dendritic spinous growth.

Acetates↗