Showing papers on "Urea cycle published in 2001"

Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function.

Abstract: Background Endogenous production of nitric oxide is vital for the decrease in pulmonary vascular resistance that normally occurs after birth. The precursor of nitric oxide is arginine, a urea-cycle intermediate. We hypothesized that low concentrations of arginine would correlate with the presence of persistent pulmonary hypertension in newborns and that the supply of this precursor would be affected by a functional polymorphism (the substitution of asparagine for threonine at position 1405 [T1405N]) in carbamoyl-phosphate synthetase, which controls the rate-limiting step of the urea cycle. Methods Plasma concentrations of amino acids and genotypes of the carbamoyl-phosphate synthetase variants were determined in 65 near-term neonates with respiratory distress. Plasma nitric oxide metabolites were measured in a subgroup of 10 patients. The results in infants with pulmonary hypertension, as assessed by echocardiography, were compared with those in infants without pulmonary hypertension. The frequencies of t...

Urea and glutamine synthesis: Environmental influences on nitrogen excretion

Abstract: The focus of this chapter is on recent developments in our understanding of the expression of the urea cycle and the roles of glutamine synthetase (GSase) and glutamine-dependent carbamoyl-phosphate synthetase (CPSase III) in ammonia detoxification in fish, with emphasis on teleosts. Marine elasmobranch fishes have an active urea cycle, synthesizing and retaining urea for the purpose of osmoregulation. Well-characterized biochemical features uniquely different from the urea cycle in ureotelic terrestrial vertebrates that have served as a reference for studies on teleost fishes are reviewed. The majority of teleost fishes are ammonotelic, that is, ammonia is simply excreted directly across the gills into the surrounding aqueous environment. But, a functional urea cycle and ureotelism have been documented in a few adult species as adaptations to unusual environmental circumstances (stress, air exposure, high pH, exposure to high concentrations of ammonia). These adaptations are reflected in altered (1) CPSase III amino acid sequences and kinetic properties, (2) regulation of the levels of gene expression, and (3) specificity of expression with respect to organ localization (e.g., expressed in muscle instead of liver) and life-cycle stage. The emerging view is that all fish likely have genes for the urea cycle enzymes; teleost fish normally do not express the urea cycle enzymes (except perhaps during embryogenesis); fish are opportunistic in variations of adapting expression of the urea cycle to local environments; and fish are highly individualistic in the mechanisms they employ for adapting to varying environmental challenges, that is, expression of the urea cycle is only one of several possible strategies.

Urea flux in beef steers: effects of forage species and nitrogen fertilization.

Abstract: The effects of two forage species and N levels on urea kinetics and whole-body N metabolism were evaluated in eight Angus steers (initial BW 217+/-15 kg). In a replicated, 4 x 4 Latin square design, steers were fed gamagrass (Tripsacum dactyloides L.) or switchgrass (Panicum virgatum L.), each of which had 56.2 (LO) or 168.5 (HI) kg of N fertilization per hectare. Diets provided adequate energy for 0.5 kg ADG. Nitrogen balance and urea kinetics were measured from d 22 to 27 of each period. Urine samples collected during intravenous infusion of bis 15N urea were used to calculate production and recycling of urea N from relative abundance of urea isotopomers. Jugular blood serum was analyzed for serum urea N (SUN). Gamagrass differed from switchgrass (P < 0.05) in daily DMI (4,273 vs 4,185 g), N intake (72 vs 67 g), DM digestibility (61.0 vs 63.6%), fecal N (30.6 vs 28.3 g/d), urine urea N (10.5 vs 8.0 g/d), and percentage of urinary N present as urea N (53.5 vs 40.0%). After adjustment for differences in N intake, fecal N still tended to be greater (P < 0.09) for gamagrass than for switchgrass. The LO differed from the HI (P < 0.01) in daily N intake (63 vs 76 g), DM digestibility (61.3 vs 63.3%), urine N (13.6 vs 25.9 g/d), and N retained as a percentage of N digested (57.3 vs 43.5%). Compared to switchgrass, gamagrass had greater SUN, N digestibility, and N digested as N level increased (forage x N level interactions, P < 0.05). As N level increased, N retention increased from 19.5 to 23.5 g/d in gamagrass and decreased from 20.5 to 18.1 g/d in switchgrass (interaction, P < 0.07). The HI group was greater than the LO intake group (P < 0.03) in endogenous production of urea N (44.4 vs 34.0 g/d), gut entry rate of urea N (31.6 vs 28.2 g/d), and the amount of urea N that re-entered the ornithine cycle (9.4 vs 7.9 g/d). However, the percentage of urea N entering the gastrointestinal tract that was recycled was constant among treatments (29.1%), indicating that almost 70% of the urea N that entered the gastrointestinal tract was potentially available for anabolic purposes of the steers as a component of microbial products that were absorbed or excreted in the feces. In summary, N levels affected N metabolism of steers more when they were fed gamagrass than when they were fed switchgrass. Although the absolute amounts of N moving through the system changed with variations in intake, the proportions remained similar, with a greater efficiency of N use at low N intakes.

Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity

Abstract: Ammonia enters the brain by diffusion from the blood or cerebrospinal fluid, or is formed in situ from the metabolism of endogenous nitrogen-containing substances. Despite its central importance in nitrogen homeostasis, excess ammonia is toxic to the central nervous system and its concentration in the brain must be kept low. This is accomplished by the high activity of glutamine synthetase, which is localized in astrocytes and which permits efficient detoxification of incoming or endogenously generated ammonia. The location also permits the operation of an intercellular glutamine cycle. In this cycle, glutamate released from nerve terminals is taken up by astrocytes where it is converted to glutamine. Glutamine is released to the extracellular fluid to be taken up into the nerve cells, where it is converted back to glutamate by the action of glutaminase. Most extrahepatic organs lack a complete urea cycle, and for many organs, including the brain, glutamine represents a temporary storage form of waste nitrogen. As such, glutamine was long thought to be harmless to the brain. However, recent evidence suggests that excess glutamine is neurotoxic. Hyperammonemic syndromes (e.g., liver disease, inborn errors of the urea cycle, Reye's disease) consistently cause astrocyte pathology. Evidence has been presented that hyperammonemia results in increased formation of glutamine directly in astrocytes, thereby generating an osmotic stress to these cells. This osmotic stress results in impaired astrocyte function, which in turn leads to neuronal dysfunction. In this review a brief overview is presented of the role of glutamine in normal brain metabolism and in the pathogenesis of hyperammonemic syndromes. MRDD Research Reviews 2001;7:280–286. © 2001 Wiley-Liss, Inc.

Ammonia detoxification and localization of urea cycle enzyme activity in embryos of the rainbow trout (Oncorhynchus mykiss) in relation to early tolerance to high environmental ammonia levels

Abstract: The present study investigated the role of ammonia as a trigger for hatching, mechanisms of ammonia detoxification and the localization of urea cycle enzymes in the early life stages of freshwater rainbow trout (Oncorhynchus mykiss). The key urea cycle enzyme carbamoyl phosphate synthetase III was found exclusively in the embryonic body (non-hepatic tissues); related enzymes were distributed between the liver and embryonic body. 'Eyed-up' trout embryos were exposed either acutely (2h) to 10 mmol l(-1) NH(4)Cl or chronically (4 days) to 0.2 mmol l(-1) NH(4)Cl. Time to hatching was not affected by either acute or chronic NH(4)Cl exposure. Urea levels, but not ammonia levels in the embryonic tissues, were significantly higher than in controls after both acute and chronic NH(4)Cl exposure, whereas there were no significant changes in urea cycle enzyme activities. Total amino acid levels in the embryonic tissues were unaltered by chronic ammonia exposure, but levels of most individual amino acids and total amino acid levels in the yolk were significantly lower (by 34-58%) than in non-exposed controls. The data indicate that trout embryos have an efficient system to prevent ammonia accumulation in embryonic tissue, by conversion of ammonia to urea in embryonic tissues and through elevation of ammonia levels in the yolk.

Localized proton MR spectroscopy in infants with urea cycle defect.

Abstract: Summary: Urea cycle defect is an inborn error of ammonium metabolism caused by a deficient activity of the enzymes involved in urea synthesis. Localized short-TE proton MR spectroscopy, performed in two infants who had citrullinemia and ornithine transcarbamylase deficiency, respectively, showed a prominent increase of glutamine/glutamate and lipid/lactate complex in both cases. N-acetylaspartate, total creatine, and myo-inositol were decreased in the infant with citrullinemia. Proton MR spectroscopy provided useful information for the diagnosis and understanding of the pathophysiology of urea cycle enzyme defect.

Ornithine carbamoyltransferase deficiency

Abstract: The death of Jesse Gelsinger on 17 September 1999 had major effects on the gene therapy community. It brought to a halt a gene therapy clinical trial at the Institute of Human Gene Therapy, University of Pennsylvania, USA and brought to a wider audience the potential clinical problems associated with this technology.1 In addition a number of clinicians became aware of Jesse's genetic disorder, ornithine carbamoyltransferase deficiency (OCTD, McKusick 311250), for the first time. OCTD is the most common disorder of ureagenesis (prevalence 1/40 000) and is inherited as an X linked trait. The OCT gene is located on the short arm of the X chromosome (Xp21.1) and over 150 mutations have been found in OCTD families. There are no common mutations and defects include gross deletions, missense and splicing mutations, as well as small insertions and deletions.2 3 The importance of detecting mutations within families lies primarily with accurate carrier detection and prenatal diagnosis, as biochemical and enzymatic methods of detection are less reliable. In addition, as enzyme activity is not expressed in either amniocytes or chorion villus biopsy material, prenatal testing had to rely on invasive fetal liver biopsy until DNA methods became available. In certain families knowledge of the mutation may help with disease prediction.4 Although our understanding of OCTD has increased greatly over recent years our abilities to treat the severe variants of this disorder remain limited. Figure 1 shows a simplified version of the urea cycle. Figure 1 The urea cycle. CPS, carbamyl phosphate synthetase; OTC, ornithine transcarbamylase; AS, argininosuccinic acid synthetase; AL, argininosuccinic acid lyase; A, arginase; *waste nitrogen molecules. Ammonia is an extremely toxic molecule and organisms have evolved a number of different ways of excreting this waste product of protein metabolism. Where water is abundant (for example, fish) ammonia is directly excreted …

Role of ureogenesis in the mud-dwelled Singhi catfish (Heteropneustes fossilis) under condition of water shortage.

Abstract: The air-breathing Singhi catfish Heteropneustes fossilis was kept inside moist peat for 1 month mimicking their normal habitat in summer and the role of ureogenesis for their survival in a water-restricted condition was studied. The ammonia excretion rate by the mud-dwelled fish increased transiently between 6 and 12 h of re-immersion in water to approximately between eight and 10-fold, followed by a sharp decrease almost to the normal level at the later part of re-immersion. The urea-N excretion by the mud-dwelled fish increased to approximately 11-fold within 0-3 h of re-immersion, followed by a gradual decrease from 9 h onwards. The rate of urea-N excretion by the mud-dwelled fish, however, remained significantly higher (approx. threefold more) than the control fish even after 36-48 h of re-immersion. Although there was a significant increase of both ammonia and urea levels in the plasma and other tissues (except ammonia in the brain), the level of accumulation of urea was higher than ammonia in the mud-dwelled fish as indicated by the decrease in the ratio of ammonia: urea level in different tissues including the plasma. The activities (units/g tissue and /mg protein) of glutamine synthetase and three enzymes of the urea cycle, carbamyl phosphate synthetase, argininosuccinate synthetase and argininosuccinate lyase increased significantly in most of the tissues (except the brain) of the mud-dwelled fish as compared to the control fish. Higher accumulation of ammonia in vivo in the mud-dwelled Singhi catfish is suggested to be one of the major factors contributing to stimulation of ureogenesis. Due to this physiological adaptive strategy of ureogenesis, possibly along with other physiological adaptation(s), this air-breathing amphibious Singhi catfish is able to survive inside the moist peat for months in a water-restricted condition.

Liver-type arginase is a highly sensitive marker for hepatocellular damage in rats.

Abstract: Hepatic enzymes in serum, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are routinely measured in serum for the diagnosis of hepatic disease; however, these enzymes are not liver specific because they are widely distributed in nonhepatic tissues. In contrast, urea cycle enzymes, i.e., liver-type arginase (ARG), ornithine carbamoyltransferase (OCT), and argininosuccinate synthase (AS), exist almost exclusively in the liver (1)(2)(3) and may serve as more specific markers of liver injury. It has been reported that some of the urea cycle enzymes leak rapidly from hepatocytes when liver cells are damaged (4)(5)(6)(7)(8)(9)(10)(11). Although there are several “hepatic marker” enzymes, including the urea cycle enzymes, it is not known which one of them is the most suitable enzyme for early detection of hepatocellular injury. To confirm the most suitable enzyme for this purpose, it is important to verify changes in the serum concentrations of urea cycle enzymes after liver damage, in comparison with enzymes in routine use. Two rat experimental models were designed: (a) a chemical liver injury model induced by carbon tetrachloride, and (b) an ischemia-reperfusion liver injury model. We measured the urea cycle enzymes ARG, OCT, and AS in sera, using procedures that we described previously (9)(12). Anti-OCT and AS IgGs were conjugated with N -hydroxysuccimidobiotin, essentially as described by Akhoundi et al. (13). These conjugates were used as second antibodies. Evaluation was based on the limited localization of the urea cycle enzymes in hepatocytes and the high specificity of our antibody. Serum activities of AST and ALT were measured by an automated blood chemistry analyzer …

Ornithine transcarbamylase deficiency unmasked because of gastrointestinal bleeding.

Abstract: Ornithine transcarbamylase (OTC) is a mitochondrial-matrix enzyme that catalyzes conversion of ornithine and carbamyl phosphate to citrulline, the second step in the urea cycle. The urea cycle is the most important pathway to detoxification of ammonia in human beings. Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder, inherited as an X-linked disorder that can cause fatal hyperammonemia in male newborns. Women with OTCD have a variable expression of their disease, the variability being determined by lyonization (random inactivation) of the X chromosome. We report a case of a 28-year-old woman who presented with hyperammonemic encephalopathy that was precipitated by a gastrointestinal bleed unmasking OTCD.

Glutamate transporter and receptor function in disorders of ammonia metabolism

Abstract: Disorders of ammonia metabolism including urea cycle enzymopathies, Reye Syndrome, and liver failure are associated with brain edema and severe neurological impairment. Excess blood-borne ammonia crosses the blood-brain barrier by diffusion as NH(3) where it interacts with various cellular processes involved in neurotransmission and brain energy metabolism. Ammonia exerts a potent effect on glutamate (AMPA) receptor-mediated neurotransmission. Ammonia also inhibits high affinity transport of glutamate by an action on astrocytic glutamate transporter expression, an action which results in increased extracellular concentrations of glutamate. Acute hyperammonemia directly activates the NMDA subclass of glutamate receptors resulting in increased intracellular Ca(2+) and increased synthesis of nitric oxide and cGMP. Chronic hyperammonemia, on the other hand, results in a loss of NMDA receptor sites. Activation of NMDA receptors in acute ammonia toxicity results in depletion of ATP in brain. Neuropathologic studies in experimental animals with congenital urea cycle disorders and severe hyperammonemia reveal evidence of neuronal cell death which is excitotoxic in nature. These findings suggest that overactivation of NMDA receptors is a significant feature of acute hyperammonemic syndromes and that antagonists of these receptors or of their signal transduction pathway enzymes such as nNOS could be beneficial in the treatment of the central nervous system manifestations (encephalopathy, brain edema) which are characteristic of hyperammonemic disorders.

Effects of exercise on nitrogen excretion, carbamoyl phosphate synthetase III activity and related urea cycle enzymes in muscle and liver tissues of juvenile rainbow trout (Oncorhynchus mykiss).

Abstract: The purpose of this study was to determine if carbamoyl phosphate synthetase III (CPSase III) and related urea cycle enzyme activities in skeletal muscle tissue of juvenile rainbow trout (Oncorhynchus mykiss) increase during short- or long-term exercise, in parallel with changes in whole-body urea excretion rates. Urea excretion was elevated by 65% in fish that swam at high-speed (50 cm/s) vs. low-speed (20 cm/s) over a 2-h period, with no significant changes in CPSase III, ornithine transcarbamoylase or glutamine synthetase activities in muscle tissue. Fish that swam for 4 days at high-speed had higher rates of ammonia excretion and GSase activity in muscle and liver tissue relative to low-speed swimmers. Calculations showed that 47-53% of excreted urea, theoretically could be accounted for by total muscle CPSase III activity in juvenile and adult trout. The data indicate that increases in the rate of urea excretion during short-term high intensity exercise are not linked to higher activities of urea cycle enzymes in muscle tissue, but this does not rule out the possibility of increased flux through muscle CPSase III and related enzymes. Furthermore, these results indicate that urea cycle enzyme activities in skeletal muscle tissue can account for a significant portion of total urea excretion in juvenile and adult trout.

The protective effect of HD-03 in CCl4-induced hepatic encephalopathy in rats

Abstract: The liver is a major parenchymal organ involved in many functional activities in the body. Hepatic encephalopathy is a syndrome characterized by increased blood ammonia level and is one of the major complications of cirrhosis. In the present study the protective effect of HD-03, a poly-herbal formulation, was evaluated against CCl4-induced hepatic encephalopathy in rats. Hepatic encephalopathy was induced in Wistar rats by administration of CCl4 at a dose of 1 mL/kg orally in liquid paraffin (1:1) twice a week for 90 days. The liver enzymes (SGPT and SGOT) and blood ammonia levels were significantly (p < 0.001) higher in the CCl4-intoxicated group compared with the untreated control group. Administration of HD-03 at a dose of 750 mg/kg orally as an aqueous suspension significantly prevented the elevation of SGPT, SGOT and blood ammonia levels. Histomorphometric evaluation of liver and brain showed a protective effect of the HD-03 treatment, thus correlating with the changes in biochemical profiles. The protective effect of HD-03 against CCl4-induced encephalopathy may be due to the improved hepatocellular function, which in turn helps in regulating the metabolism of ammonia. However, further studies are required to measure the activity of enzymes involved in the urea cycle and brain aromatic amino acids in order to elucidate the exact mechanism of action of HD-03.

Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry.

Abstract: Argininosuccinate lyase (ASL) deficiency (McKusick 207900) is an inborn error of the urea cycle. The leading symptom is progressive hyperammonaemia, which is a life-threatening condition, particularly in patients with a neonatal onset. Early diagnosis and treatment of the hyperammonaemia are necessary to improve survival and the long-term outcome of ASL-deficient patients. Currently, the diagnosis of ASL deficiency is based on the measurement of urea cycle intermediates and amino acids by automated quantitative ion exchange chromatography in plasma and urine. Here, we report a newborn presenting with coma and severe hyperammonaemia. ASL deficiency was suspected on the basis of an adapted tandem mass spectrometric (MS-MS) procedure which allows determination of argininosuccinate in addition to the amino acids in serum samples. MS-MS measurements revealed a characteristic increase of argininosuccinate, a moderate increase of citrulline, and lowered levels of arginine and ornithine in the serum of the patient. The diagnosis was confirmed by the detection of a novel homozygous frameshift mutation in exon 14 of the argininosuccinate lyase gene. We propose MS-MS as a diagnostic tool suitable for the rapid detection of specific alterations in the amino acid spectra caused by ASL deficiency.

Amino Acid Degradation

Abstract: Amino acids are valuable metabolic fuels, providing a supply of both nitrogen and carbon for intermediary metabolism and energy for growth. Controlled degradation of amino acids is important in the maintenance of the carbon–nitrogen balance. It is becoming increasingly apparent that imbalance in amino acid degradation can have important consequences for both development and disease. Generally, the first step in degradation of amino acids results in the amino group either being incorporated into other nitrogenous compounds or being excreted as ammonia or urea, while the carbon skeleton is catabolised to one of a few common metabolic intermediates. Thus, an understanding of amino acid degradation provides knowledge of the interrelationships between metabolic pathways and helps explain some of the clinical features when deficiencies in amino acid metabolism occur. Key Concepts Amino acids are important growth substrates for microorganisms. Tight control of amino acid degradation and cycling maintains the C–N balance. Glutamate is a key central amino acid in maintenance of the C–N balance. The first step in amino acid degradation is removal of the α-amino group. Key steps in amino acid degradation include deamination, catalysed by pyridoxal-phosphate-dependent transaminases, oxidoreductases or carbon–oxygen lyases, decarboxylase reactions and carbon skeleton rearrangements catalysed by isomerases. Carbon skeletons arising from amino acid breakdown are channelled into central metabolism. Production and excretion of urea and uric acid by animals and birds and reptiles, respectively, avoids the accumulation of toxic levels of ammonia in blood and tissues. Metabolic products derived from l-serine are essential for cell proliferation and a functional nervous system. Absence of key enzymes, or imbalance in amino acid degradation, leads to severe disease states, such as phenylketonuria and methylmalonic aciduria. Keywords: amino acids; metabolism; urea cycle; pyridoxal phosphate; inborn errors in metabolism

High serum pancreatic secretory trypsin inhibitor before onset of type II citrullinemia.

Abstract: Type II citrullinemia (CTLN2, Online Mendelian Inheritance in Man [OMIM] #603471) is an enzyme deficiency most often characterized by adult-onset recurrent encephalopathy associated with hyperammonemia, coma, and severe brain edema evolving into a subacute progressive or recurrent course.1 CTLN2 is characterized by a selective deficiency of liver-specific argininosuccinate synthetase protein in the urea cycle, but it is believed that the argininosuccinate synthetase gene is not a cause of this disorder.2 Genetic and biochemical studies of families with CTLN2 recently showed that the defect localized to chromosome 7q21.3 and suggested that the disorder is caused by a mutation of the gene SLC25A13 encoding the protein citrin, which is expressed most abundantly in the liver.3 Citrin is believed to work as a calcium-dependent mitochondrial solute transporter with a crucial role in urea cycle function. Patients with CTLN2 have significantly increased expression of pancreatic secretory trypsin inhibitor (PSTI) mRNA in the liver and high PSTI levels in serum.4,5⇓ PSTI is a secretory protein, and serum PSTI has been proposed as a …

Compensatory changes in enzymes of arginine metabolism during renal hypertrophy in mice.

Abstract: The present study investigates enzyme activities of the urea cycle, transamidinase and ornithine–proline inter-conversion in the hypertrophied kidney after unilateral nephrectomy in mice. Surgical removal of the left kidney in mice led to compensatory enlargement of the right kidney after 1 and 14 days. This renal growth was associated with an increase in glomerular volume (but not number) and enlargement of the proximal convoluted tubules. The total renal protein content increased in proportion to the increase in kidney weight, but the protein per gram weight of kidney did not change. The specific activity of only ornithine aminotransferase (OAT), the rate-limiting enzyme in the conversion of ornithine to proline, increased in 2 weeks of hypertrophy. The specific activity of all other enzymes was unchanged. However, the total enzyme activity per kidney of all the enzymes, without exception, was elevated in the hypertrophied kidney. While the increase in total OAT activity was much more than the increase in kidney weight, all other enzymes increased more or less in proportion to the increase in renal mass. The results suggest that compensation in OAT activity to chronic reduction in renal mass was complete, but only partial in the case of other enzymes.

Influence of alimentary zinc deficiency on nitrogen elimination and enzyme activities of the urea cycle

Abstract: Influence of alimentary zinc deficiency on nitrogen elimination and activities of urea cycle enzymes This study was conducted to investigate whether the hyperammonaemia shown in earlier zinc-deficiency experiments was the result of disturbed enzyme activities of the urea cycle. For this study 36 male Sprague-Dawley rats with an average body weight of 85 g were divided into three experimental groups of 12 animals each. Group 1 received the semisynthetic zinc-deficient diet (AIN-93G; 1.2 mg Zn/kg DM) ad libitum over 33 experimental days. Group 2 received the zinc-sulphate-supplemented control diet (60 mg Zn/kg DM) ad libitum and group 3 received the same diet matched to the feed intake of the zinc-deficient rats. Alimentary zinc deficiency reduced the zinc concentration and the activity of the alkaline phosphatase in serum by 75 and 67%, respectively. The activity of the glutamate dehydrogenase and the concentrations of ammonia and urea in the serum of the zinc-deficient rats showed no significant differences compared with pair-fed control rats. On the other hand the hepatic activity of the mitochondrial localized glutamate dehydrogenase of the zinc-deficient rats was significantly increased and the carbamoylphosphate synthetase and ornithine carbamoyltransferase were reduced about half in comparison with both control groups. The activities of the cytosolic liver enzymes such as argininosuccinate synthetase, argininosuccinase and arginase were again significantly increased in zinc-deficient rats compared with both control groups. The increased hepatic activity of the glutamate dehydrogenase possibly led to an enhanced NH(3) elimination in addition to urea synthesis. The typical reduction of feed intake in consequence of zinc deficiency is therefore not the cause of hyperammonaemia due to disturbed urea synthesis, as has been hypothesized in earlier studies.