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PubMed1992

Synthesis of nucleic acids in blood cells in mice after irradiation with gamma rays.

In the blood of mice irradiated with a single total-body dose of 8 Gy gamma rays we examined the concentration of nucleic acids and incorporation of 3H-thymidine and 14C-orotic acid. The concentration of nucleic acids, above all that of DNA in the so-called blood leukocyte mass dropped significantly in the course of the first three days after irradiation. Recovery began in the course of the second week following irradiation. On day 21 after irradiation, DNA concentration was found to be recovered temporarily and RNA concentration to exceed the control values. The increase of incorporation of 3H-thymidine confirmed an increased incidence of DNA synthesizing cells in the blood within days 12-15 after irradiation. Since the increase of incorporation of 3H-thymidine into DNA was not preceded by an increase of incorporation of 14C-orotic acid into RNA, we presume that the DNA synthesizing cells in the blood of irradiated animals do not represent the stimulated lymphocytes but circulating hemopoietic cells. Therefore, the examination of DNA synthesis in blood cells enables to record the course of bone marrow regeneration after irradiation or after application of hemopoiesis depressing substances.

Animals↗
PubMed1981

Orotic aciduria caused by feeding excess lysine to growing rats.

Two 14-day factorial experiments were performed to assess changes in growth, feed intake and urinary orotic acid excretion of weanling male Sprague-Dawley rats. The dietary variables investigated included the percentage of dietary casein in the basal diet, its supplementation with 5% lysine-HCl or 1% arginine-HCl and sucrose or two parts dextrin and one part sucrose as the only form of carbohydrate. The response to 5% supplemental lysine was strikingly similar to that seen with arginine-free diets. With 5% lysine added to 15% casein diets, growth decreased 25% and feed efficiency 20% while orotic acid excretion increased significantly. When 5% lysine was added to diets with 7.5 or 30% casein, these responses were smaller and were prevented by the simultaneous feeding of 1% arginine. Growth depression by lysine was partially reversed by replacing two-thirds of the dietary sucrose with dextrin. When unsupplemented, the casein diets containing only sucrose as carbohydrate supported less growth than the same diets containing the dextrin sucrose mixture. This difference was abolished by supplementation with 1% arginine, suggesting that sucrose increases arginine requirements for optimal growth. The data are consistent with the conclusion that orotic acid excretion is a useful index for determining when lysine excess is producing a functional deficiency of arginine.

Ammonia↗
PubMed1986

Ammonia toxicity: comparative protective effect of various arginine and ornithine derivatives, aspartate, benzoate, and carbamyl glutamate.

Ornithine and arginine compounds were highly effective in preventing an increase in blood ammonia and in preventing or minimizing encephalopathy after acute subcoma, coma-inducing, or lethal doses of NH4+. Similar protection was seen after subacute loading with glycine. Ornithine ketoacid derivatives were no more effective than ornithine alone or ornithine glutamate. Ornithine appeared to be a little more effective than arginine, but the differences were slight. Aspartate and glutamate alone were ineffective. Carbamyl glutamate was much less effective than either ornithine glutamate or arginine glutamate. Orotic acid excretion was markedly increased in the presence of excess NH4+. This increment was eliminated with ornithine or arginine, although the reduction with arginine was unpredictably erratic. Aspartate increased the orotic acid excretion and the amount of urea formed. Sodium benzoate was borderline in its effect on the blood ammonia and on orotic acid excretion.

Ammonia↗
PubMed1994

Dietary supplementation of L-arginine ameliorates renal hypertrophy in rats fed a high-protein diet.

Ingestion of a high-protein diet or intravenous administration of amino acids is associated with an increase in glomerular filtration rate (GFR). It can also lead to renal hypertrophy, and, if sustained, may cause glomerular sclerosis. L-Arginine administration ameliorates the progression of renal disease in rats with subtotal nephrectomy and prevents the increase in GFR observed in rats with experimental diabetes. The present study examines the potential effect(s) of L-arginine administration (1%) in the drinking water on the renal hypertrophy that occurs in rats fed a high-protein diet for 1 month. Four groups of female Sprague-Dawley rats, six in each group, were studied (95 +/- 1 g). Groups 1 and 2 were fed a low-protein diet (12% casein, 0.504% L-arginine); Group 1 was given tap water, whereas Group 2 was given tap water supplemented with L-arginine. Groups 3 and 4 were fed a high-protein diet (40% casein, 1.68% L-arginine); Group 3 was given tap water, whereas Group 4 was given tap water supplemented with L-arginine. The rats had free access to food and water during the study period. The kidney weight and the kidney to body weight ratio of rats of Group 3 were significantly greater than in the other groups of rats. Renal hypertrophy was prevented in the rats of Group 4. The excretion of orotic acid in the urine, an index of L-arginine deficiency, was significantly greater in rats of Group 3 than in rats of Group 4. Thus, the renal hypertrophy that occurs in rats fed a high-protein diet was decreased in rats given L-arginine supplementation in the drinking water. This effect was associated with less excretion of orotic acid in the urine in rats given L-arginine. A relative deficiency of L-arginine may occur during high-protein feeding that may shunt nitrogen metabolism from the urea cycle to the orotic acid pathway.

Animals↗
PubMed1998

Neuroprotective effect of YM-39558 in focal cerebral ischemia in cats.

We studied the effect of YM-39558, orotic acid ethylester, in a focal cerebral ischemia model in anesthetized cats. YM-39558 has good permeability across the blood brain barrier, and in the brain is hydrolyzed to orotic acid, the main active substance. Cats were subjected to permanent occlusion of the middle cerebral artery (MCA) for 6 h, then killed and examined histologically. Treatment with YM-39558 (intravenous infusion of 11.8 mg (10 mg as orotic acid)/6 ml per kg per h) starting 15 min after MCA occlusion markedly reduced the volume of ischemic damage (from 2450 +/- 82 mm3 of the cerebral hemisphere in the saline-treated cats to 1644 +/- 123 mm3 in the YM-39558-treated cats, P < 0.01). In contrast, YM-39558 (2.26 and 1.18 mg/0.8 ml per kg per h) showed no significant protective effect on ischemic damage. No significant differences were observed between saline- and YM-39558-treated cats concerning physiological variables including brain temperature. This evidence for the neuroprotective efficacy of YM-39558 in gyrencephalic species suggests its therapeutic potential in the treatment of stroke in humans.

Animals↗
PubMed2007

The influence of pharmacogenetics on fatty liver disease in the wistar and kyoto rats: a combined transcriptomic and metabonomic study.

Although fatty liver disease is caused by a number of toxicological insults and the metabolic syndrome, the exact mechanisms by which many of these pathophysiological stimulii induce fatty liver are unknown. The rapid and profound steatosis caused by orotic acid, resulting from an impairment in the production of ApoB, has been investigated in the Wistar strain rat using a combined transcriptomic and metabonomic/metabolomic approach. Analysis of liver tissue from rats exposed to orotic acid for 1, 3, and 14 days was performed by DNA microarrays and high resolution 1H NMR spectroscopy based metabonomics of both tissue extracts and intact tissue (n = 3). Data were analyzed using a combination of ANOVA and principal components analysis, used as a data reduction tool to visualize the most perturbed transcripts and metabolites. Orotic acid produced a profound 8-fold increase in total lipids, and in particular increases in resonances associated with polyunsaturated fats (CH=CH and CH2CH=CH groups). This was accompanied by increases in the concentrations of trimethylamine-oxide (TMAO), betaine, choline, and phosphocholine, as well as a relative decrease in glucose and glycogen. At the transcriptional level, perturbations were detected in both oxidative stress and osmoregulation/pH homeostasis. However, this contrasts with a previous transcriptomic/metabolic study of fatty liver disease in a combined data set of Wistar (out-bred) and Kyoto (in-bred) strains of rats, with only 4 transcripts being found to be in common between the two analyses. This emphasizes the need to understand how strain background interacts with a given toxic lesion or genetic modification.

Animals↗
PubMed1979

Altered erythrocyte pyrimidine activity in vitamin B12 or folate deficiency.

The net activity of orotidylic pyrophosphorylase and decarboxylase, sequential enzymes which catalyse the formation of uridine monophosphate from orotic acid in de novo pyrimidine biosynthesis, has been evaluated in erythrocytes of patients with folate or cobalamin deficiency. In patients with normoblastic haemopoiesis and normal cobalamin and folate status a direct relationship exists between the maturity of the peripheral blood erythrocyte population, as indicated by G6PD activity, and net orotidylic activity. In contrast in cobalamin or folate deficiency this co-ordinate relationship is not observed and net orotidylic activity is relatively reduced. Fractionation of erythrocytes by centrifugation demonstrates that this inordinately low orotidylic activity consistently occurs in the young erythrocyte population and is reversed by specific replacement therapy. In vitamin B12 or folate deficiency an impressive array of evidence now exists to implicate altered folate metabolism for the observed alterations in purine and pyrimidine metabolism (Das & Herbert, 1976). Of these changes the cornerstone defect resulting in megaloblastic maturation is impaired methylation of deoxyuridine monophosphate to thymidine monophosphate (Hoffbrand et al, 1976). In this context the reduced serum uridine plus uracil levels in patients with vitamin B12 deficiency (Parry & Blackmore, 1976) and the haematological response of these patients to orotic acid therapy (Rundles & Brewer, 1958) are not readily explicable. Since the conversion of orotic acid to uridine monophosphate depends on the integrity of the coupled activities of orotidylic pyrophosphorylase and decarboxylase, this study has quantitated this capacity in peripheral blood erythrocytes in patients with vitamin B12 or folate deficiency.

Erythrocytes↗
PubMed1994

Decreased hyperammonaemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase.

Mice with the X-chromosomal sparse-fur (spf) mutation are an animal model of some hereditary deficiencies of ornithine carbamoyltransferase (OCT) in man. Orotic aciduria and hyperammonaemia are the most conspicuous metabolic changes in these diseases. Selective inactivation of ornithine aminotransferase (OAT) by 5-fluoromethylornithine raises endogenous ornithine concentrations so that citrulline formation is effectively catalysed by the aberrant OCT, in spite of its low affinity for ornithine. As a consequence, blood and tissue ammonia concentrations and orotic acid excretion are reduced near to normal values, and the abnormal amino acid patterns in blood, brain and liver are normalized. Selective inactivation of OAT seems a promising therapeutic approach in some hereditary OCT deficiencies, and a total that may allow us to clarify the role of ammonia and orotic acid in the development of nanism and abnormal behaviour in spf mutant mice.

Amino Acids↗
PubMed2000

Large-scale production of CMP-NeuAc and sialylated oligosaccharides through bacterial coupling.

A large-scale production system of cytidine 5'monophospho-N-acetylneuraminic acid (CMP-NeuAc) and sialyloligosaccharides was established by a whole-cell reaction through the combination of recombinant Escherichia coli strains and Corynebacterium ammonia-genes. For the production of CMP-NeuAc, two recombinant E. coli strains were generated that overexpressed the genes of CMP-NeuAc synthetase and CTP synthetase, respectively. C. ammoniagenes contributed to the formation of UTP from orotic acid. CMP-NeuAc was accumulated at 27 mM (17 g/l) after a 27-h reaction starting with orotic acid and N-acetylneuraminic acid. When E. coli cells that overexpressed the alpha-(2-->3)-sialyltransferase gene of Neisseria gonorrhoeae were put into the CMP-NeuAc production system, 3'-sialyllactose was accumulated at 52 mM (33 g/l) after an 11-h reaction starting with orotic acid, N-acetylneuraminic acid, and lactose. Almost no oligosaccharide byproducts other than 3'-sialyllactose were observed after the reaction. The production of 3'-sialyllactose at a 5-l jar fermenter scale was almost the same as that at a beaker scale, which indicated the high potential of the 3'-sialyllactose production on an industrial scale.

Biotechnology↗
PubMed1975

Interconversion of different molecular weight forms of human erythrocyte orotidylate decarboxylase.

Orotidylate decarboxylase has been purified approximately 300-fold from human erythrocytes. It was shown to exist in three molecular weight forms, a probable monomer of molecular weight 62,000, a dimer, and a tetramer. Conversion of the monomer to higher molecular weight forms was associated with increased stability to thermal inactivation and was promoted by a number of low molecular weight compounds, including orotic acid and competitive inhibitors of the enzyme. Orotic acid phosphoribosyltransferase co-purified with the decarboxylase but was much more susceptible to inactivation. The partially purified orotidylate decarboxylase showed a triphasic Lineweaver-Burk plot when examined over a wide range of substrate concentrations. The separated molecular weight forms gave linear double reciprocal plots with Km values corresponding to the three values obtained with the erythrocyte enzyme preparation. The values obtained were 25, 3, and 0.6 muM for the monomer, dimer, and tetramer forms, respectively.

Carboxy-Lyases↗
PubMed1979

Orotic aciduria and increased nitrogen catabolism in rats.

In vitro incorporation of [14C] bicarbonate into orotic acid by rat liver slices was used to study the rate of orotic acid (OA) biosynthesis in the presence of physiological (0.73 mM) and saturation concentrations (5 mM) of NH4Cl. The influence of body size on OA synthesis in rats fed purified L-amino acid diets with (C) or without (-Arg) was examined. OA biosynthesis was significantly greater at both NH4Cl concentrations examined in liver slices obtained from -Arg rats for all sizes of rats. A linear decrease (r = 0.92) in OA synthesis as a function of body size was observed for rats fed either of the diets. The rate of OA biosynthesis was also found to increase linearly (r = 0.98) in livers from rats fed increasing dietary protein when determined by incubation with physiological concentrations of NH4Cl. OA biosynthesis was also found to increase with increase in length of fasting. Alteration in urinary OA and urea confirm these rates of synthesis. These results support the hypothesis that when the urea cycle is overtaxed, carbamyl phosphate (CP) synthesized intramitochondrially by CP synthetase I may be shunted into pyrimidine biosynthesis.

Aging↗
PubMed1978

HCN: a plausible source of purines, pyrimidines and amino acids on the primitive earth.

Dilute (0.1 M) solutions of HCN condense to oligomers at pH 9.2. Hydrolysis of these oligomers yields 4,5-dihydroxypyrimidine, orotic acid, 5-hydroxyuracil, adenine, 4-aminoimidazole-5-carboxamide and amino acids. These results, together with the earlier data, demonstrate that the three main classes of nitrogen-containing biomolecules, purines, pyrimidines and amino acids may have originated from HCN on the primitive earth. The observation of orotic acid and 4-aminoimidazole-5-carboxyamide suggests that the contemporary biosynthetic pathways for nucleotides may have evolved from the compounds released on hydrolysis of HCN oligomers.

Amino Acids↗
PubMed1976

Anemia of azaribine in the treatment of psoriasis.

Azaribine is an effective agent in the treatment of psoriasis. In this investigation the extent of clinical dermatologic remission appeared to correlate with the degree of metabolic block induced by 6-azauridylic acid, as quantitated by the urinary excretion of orotic acid and orotidine, and the development of anemia. Following azaribine therapy there was a coordinate rise of the specific activities of erythrocyte orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. There was no correlation between the pretreatment activity of these enzymes and the clinical response to azaribine. The anemia of azaribine therapy was mile and of a megaloblastic type. Uridine effectively corrected the azaribine-induced anemia, but led to exacerbation of the patients' psoriasis. Following uridine therapy there was a reduction in the urinary excretion of orotic acid and orotidine, presumable reflecting end-product inhibition or repression of the first steps of a repeated pyrimidine biosynthesis.

Adult↗
PubMed1986

Clinical and laboratory study in 22 patients with inherited hyperammonemic syndromes.

Twenty-two patients with inherited hyperammonemic syndromes are presented. These patients represent 22 different families. The diagnosis was based mainly on family history, blood ammonium levels, acid base balance, urinary orotic acid, urinary and plasma amino acids and organic acids. The final diagnosis was confirmed by determination of liver enzyme activity. In 12 patients (54%), the first clinical manifestations were noticed after the neonatal period; 7 patients (31%) were diagnosed after infancy, and 8 (23%) after the age of 8 years. Two patients who represent the late-onset group of inherited hyperammonemic syndromes are presented in detail. The three most common diagnoses were ornithine transcarbamoylase deficiency, carbamoyl phosphate synthetase deficiency, and lysinuric protein intolerance, which comprised 59% of the diagnosed patients. Our data, based on one of the largest series reported, reveal a relatively large percentage of late-onset inherited hyperammonemic syndromes as compared with previous reports.

Amino Acid Metabolism, Inborn Errors↗
PubMed1973

Qualitative and quantitative aspects of the biosynthesis of ribonucleic acid and of protein in the liver and the lung of the Syrian golden hamster.

1. The incorporation of orotic acid and of uridine into total RNA was measured in vivo in liver and lung of the Syrian golden hamster. Specific activities of total acid-soluble UMP were measured in both organs. An estimation of the rate of RNA biosynthesis showed that hamster lung synthesizes RNA at about one-half of the rate of that of hamster liver. 2. The apparent K(m) and V(max.) values of a few enzymes involved in pyrimidine biosynthesis were measured in the 100000g supernatants of liver and lung. The apparent K(m) values were very similar in both organs. From the estimated V(max.,) it was concluded that hamster lung cells have less capacity to metabolize orotic acid than have liver cells. 3. A time-response and a dose-response study showed that actinomycin D inhibits pulmonary RNA synthesis as efficiently as hepatic RNA synthesis. 4. Protein synthesis, measured as the incorporation of leucine, was inhibited in both organs 30min after a dose of 2mg of cycloheximide/kg. The dose-response patterns were similar in both liver and lung 3h after cycloheximide. 5. It is concluded that RNA and protein synthesis in vivo in hamster lung are very similar to the corresponding reactions in liver. Alterations of RNA and protein synthesis by toxic agents can therefore be evaluated in lung with a similar approach to that used to study the pathological biochemistry of liver.

Animals↗
PubMed1989

Expression of N-acetylglucosaminyltransferase III in hepatic nodules generated by different models of rat liver carcinogenesis.

Our earlier studies revealed that N-acetylglucosaminyltransferase III (GnTase III), which catalyzes the insertion of a bisecting N-acetylglucosamine (bi-Gn) in the complex-type N-linked glycans of cellular glycoproteins, is present in hepatic nodules promoted by the orotic acid model. Neither the bi-Gn residues nor the activity of GnTase III is detectable in normal livers and in the surrounding non-nodular liver of the rat. The present study was designed to find out whether an expression of activity of GnTase III is a phenotypic property characteristic of hepatic nodules or simply unique to nodules produced by the orotic acid model. Fischer male 344 rats were initiated with two different carcinogens namely 1,2-dimethyl-hydrazine or diethylnitrosamine and promoted by other models such as the resistant hepatocyte model and the choline deficient diet model, in addition to the orotic acid model. The hepatic nodules generated by these three different models and hepatocellular carcinomas exhibited significant levels of activity of GnTase III while non-nodular surrounding liver, regenerating liver after 2/3 partial hepatectomy or livers of age and sex matched control rats, had no detectable activity. The detection of the activity of GnTase III in nodules and in cancer is in agreement with the presence of bi-Gn residues reported in gamma-glutamyltranspeptidase of cancer tissues of rats. These results are consistent with the conclusion that the expression of GnTase III is activated during hepatocarcinogenesis and is not related to any particular initiator or promoter.

Animals↗