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PubMed1997

Enzymatic production of pyrimidine nucleotides using Corynebacterium ammoniagenes cells and recombinant Escherichia coli cells: enzymatic production of CDP-choline from orotic acid and choline chloride (Part I).

Enzymatic production of cytidine diphosphate choline (CDP-choline) using orotic acid and choline chloride as substrates was investigated using a 200-ml beaker as a reaction vessel. When Cornybacterium ammoniagenes KY13505 cells were used as the enzyme source, UMP was accumulated up to 28.6 g/liter (77.6 mM) from orotic acid after 26 h of reaction. In this reaction, UDP and UTP were also accumulated, but CTP, a direct precursor of CDP-choline, was not accumulated sufficiently. Escherichia coli JF646/pMW6 cells, which overproduce CTP synthetase by selfcloning of the pyrG gene, were used together with cells of KY12505 for the enzymatic reaction using orotic acid as a substrate. CTP was produced at 8.95 g/liter (15.1 mM) after 23 h of this reaction. To produce CDP-choline, two additional enzyme activities were needed. E. coli MM294/pUCK3 and MM294/pCC41 cells, which express a choline kinase from Saccharomyces cerevisiae (CKIase; encoded by the CKI gene) and a cholinephosphate cytidylyltransferase from S. cerevisiae (CCTase; encoded by the CCT gene) respectively, were added to this CTP-producing reaction system. After 23 h of the reaction using orotic acid and choline chloride as substrates, 7.7 g/liter (15.1 mM) of CDP-choline was accumulated without addition of ATP or phosphoribosylpyrophosphate (PRPP). ATP and PRPP required in the CDP-choline forming reaction system are biosynthesized by those cells using glucose as a substrate.

Carbon-Nitrogen Ligases↗

PubMed1980

[Uptake and incorporation of 3H-orotic acid in isolated perfused rat liver].

3H-orotic acid incorporation into RNA and the level of RNA polymerase activity in isolated rat liver perfused for 5 hrs were investigated. In spite of a dramatic decrease in 3H-orotic acid uptake by liver cells during perfusion, a constant rate of RNA synthesis was observed. Moreover, RNA polymerase I and II activities were not affected by a 5-hr perfusion. It is suggested that isolated perfused rat liver can be used to study direct effects of hormones and drugs on RNA synthesis.

Animals↗

PubMed2002

Dietary orotic acid increases 1 ,2-diacylglycerol level and lowers superoxide dismutase activity in rat liver.

The effects of the dietary addition of orotic acid were studied on lipid levels in the rat liver and serum, 1,2-diacylglycerol levels in some organs, activities of antioxidant liver enzymes (superoxide dismutase, glutathione peroxidase, and catalase), and serum enzyme activities (ornithine carbamoyltransferase and alanine aminotransferase), after feeding for 0, 7, 14, and 21 d, respectively. Rats on the orotic acid diet accumulated more liver total lipids, triacylglycerol, and phospholipids than those on the basal diet. However, the levels of serum triacylglycerol and phospholipids of those rats were markedly decreased after 7, 14, and 21 d on the diet. Dietary orotic acid increased the 1,2-diacylglycerol levels in the liver of rats fed for 14 or 21 d, but not in the ileum of small intestine, vastus lateralis muscle, and heart. The addition of orotic acid lowered the activities of liver total and Cu,Zn-superoxide dismutase after feeding for 7, 14, and 21 d. The serum ornithine carbamoyltransferase activity after 14, and 21 d and that of serum alanine aminotransferase after 7, 14, and 21 d were increased. These data suggested that the increase in the activities of serum enzymes tested may result from liver damage induced by the marked accumulation of liver lipids and possibly from the increased superoxide anion because of the decreased activities of hepatic superoxide dismutase by orotic acid feeding.

Alanine Transaminase↗

PubMed2003

Functions of a chitosan-orotic acid salt in the gastrointestinal tract.

A chitosan (CS)-orotic acid salt (CS-OT) was prepared, and the release of orotic acid (OT) from CS-OT as well as the adsorption of bile acids by CS-OT was investigated in vitro. The amount of OT released from CS-OT was about 2-2.7 micromol/mg CS-OT and this changed depending on the species of CS. CS-OT also adsorbed bile acids and the amount increased incrementally according to the number of amino group contained in CS. Furthermore, CS-OT was given to rats as feed in order to investigate the influence on serum cholesterol levels. A decrease in serum cholesterol levels was observed in the group, which was fed a diet containing CS-OT or CS for 1-2 weeks, but no differences in body weight changes were recognized. Therefore, CS-OT may be applied to treating hyperlipidemia.

Adjuvants, Pharmaceutic↗

PubMed1995

Quantification of orotic acid in dried filter-paper urine samples by stable isotope dilution.

A rapid, sensitive, and specific method for quantification of orotic acid from dried filter-paper urine samples is described. The method involves stable isotope dilution with 1,3-[15N2]orotic acid analysis by gas chromatography-mass spectrometry. The assay is sufficiently sensitive to be used with solvent extraction techniques commonly used for urinary organic acid analysis. Extraction efficiencies of both native and isotopic orotic acid from dried filter paper and from water were 31% and 28%, respectively. The concentration of orotic acid in dried filter-paper urine specimens from 50 healthy controls was 1.1 +/- 0.67 (mean +/- SD) mmol/mol of urinary creatinine. The same 50 urine samples, analyzed directly from a 5-mL aliquot of liquid urine, gave values of 0.93 +/- 0.51. The correlation coefficient between the results obtained by the two different collection methods was 0.87. Age-related reference values in filter-paper samples are also reported. The concentrations, which are normalized to urinary creatinine, decrease with age. This method is applicable to rapid screening for urea cycle disorders and may also be used for carrier testing of ornithine transcarbamylase deficiency.

Adolescent↗

PubMed1980

An automated method for the determination of orotic acid in the urine of children being screened for metabolic disorders.

Urinary orotic acid is believed to be a valuable probe for early diagnosis of inborn errors of metabolism leading to hyperammonemia and increased pyrimidine synthesis. For the purpose of our urinary mass screening programme, we developed an automated colorimetric method which is reliable in the range of 1 to 50 micrograms/ml orotic acid and allows analyses at a rate of 160 samples per hour. Preliminary results are presented which illustrate that various disorders can be recognized by measuring orotic acid in urine.

Autoanalysis↗

PubMed1999

Determination of urinary orotic acid and uracil by capillary zone electrophoresis.

We describe a simple method for measuring orotic acid and uracil concentration in urine by capillary zone electrophoresis in 20 mM Na-borate buffer, pH 9.2. The method was applied for studying a patient with HHH (hyperomithinemia, hyperammonemia and homocitrullinuria) syndrome. A high value of uracil excretion was found during periods of relatively low orotic acid excretion and normal ammonemia. The orotic acid level in urine was increased by increasing protein intake.

Amino Acid Metabolism, Inborn Errors↗

PubMed1984

The effect of 5-fluoroorotic acid on the early labelling of nucleotides and RNA in whole liver and of RNA in subnuclear fractions in rats given 3H-orotic acid.

Male white rats were given either orotic acid or 5-fluoroorotic acid 60 min, and 3H-orotic acid 3 1/2 min before sacrifice. Liver nucleotides were analyzed by isotachophoresis. The (F)UTP pool increased to the same extent in both groups and showed the same specific labelling. The RNA synthesis, as measured by nmol of UTP entering RNA-UMP/g wet liver tissue was significantly lower in fluoroorotic acid treated rats. In the nucleolar fraction there was an increase in the RNA/DNA ratio, a decrease in the specific RNA labelling and an essentially unaltered specific labelling of RNA/microgram/DNA. The effect on the specific labelling of RNA/microgram DNA was the same in the nucleolar fraction and the nucleolar-free pellet, suggesting that the transcription of RNA in these two fractions proceeded in a similar way. There was a slight increase in the specific RNA labelling of the supernatant subnuclear fraction, containing low-molecular weight RNA. Incorporation into UDP-hexoses and UDP-N-acetylhexosamine was unchanged.

Animals↗

PubMed1979

[Effect of orotic acid on reparative processes in the lungs following pneumonectomy].

The effect of orotic acid on pulmonary regeneration has been studied in mature rats after left-sided pneumonectomy. A complex morphometric analysis of the pulmonary parenchyma during the process of compensatory-hypertrophic rearrangement has been carried out; mitotic activity of cells in the interalveolar septae, peculiarities of DNA synthesis and those of enzymatic status in lymphocytes of the peripheral blood have been determined. As the investigations have demonstrated, the administration of orotic acid during the postoperative period contributes to a more complete regeneration of the lung volume, alveolar surface, results in formation of new alveoli, prevents the development of morphologic long-term decompensation following pneumonectomy. Activation of the alveolar cells proliferation and increased DNA synthesis are the main stimulating effects of orotic acid. Certain correlative connections are revealed between the course of pulmonary regenerative processes and the enzymic status of circulating lymphocytes.

Animals↗

PubMed1979

Cytosine and orotic acid in urine of immunodeficient children.

We describe procedures for determining cytosine and orotic acid in urine. We determine cytosine by cation-exchange analysis with either HCl or pH 5.2 buffer as eluent. Orotic acid is first separated by an anion-exchange separative procedure; after lyophilization, the product is subjected to "high-pressure" liquid chromatography for further separation and detection. We analyzed urine from normal subjects and from immunodeficient children. Three children with severe combined immunodeficiency had increased levels of cytosine in urine (23-160 mmol/mol creatinine); one child with severe combined immunodeficiency and two children with other immunodeficiencies had normal urinary levels (less than 2 mmol/mol creatinine). Orotic acid excretion in urine was normal (1-5 mmol/mol creatinine) in all of th immunodeficient children. We discuss the possible significance of the increased cytosine excretion in the three children with severe combined immunodeficiency.

Child↗

PubMed1985

Effect of dietary orotic acid on the levels of liver and blood NAD in rats.

The effect of dietary orotic acid on the levels of liver and blood NAD in young rats was investigated. Weanling rats were fed on a nicotinic acid-free, 20% casein diet containing 0% (control diet) or 1% orotic acid (test diet) for 32 days. Retardation of growth, development of fatty liver and enlargement of liver were observed in the test group in comparison with the control group. In the test group, the amounts of quinolinic acid, niacin, NAD and N1-methylnicotinamide, and the activities of quinolinate phosphoribosyltransferase, nicotinamide mononucleotide adenylyltransferase, nicotinamide methyltransferase and NAD synthetase expressed in terms of g liver were significantly decreased compared to the control group. When these values were expressed in terms of whole liver, a significant difference was observed in the content of NAD and the activity of NAD synthetase between the control and the test groups. The activity of aminocarboxymuconate-semialdehyde decarboxylase expressed in terms of whole liver was about 2-fold higher in the test group than in the control group, but was not significantly different. The levels of NAD in blood as well as in liver were significantly lower in the test group than in the control group. Urinary excretions of quinolinic acid, niacin and N1-methylnicotinamide were also reduced in the test group. These results are discussed in the light of the reported effect of orotic acid in lowering the level of ATP in liver.

Animals↗

PubMed1997

Post-ischaemic treatment with orotic acid prevents neuronal injury in gerbil brain ischaemia.

We studied the effects of orotic acid, a precursor of pyrimidine nucleotide, on delayed neuronal death of hippocampal CA1 neurones induced by global cerebral ischaemia in Mongolian gerbils. Neuronal damage was significantly reduced in animals treated with orotic acid 2 h before ischaemia at doses of 100, 200 or 300 mg kg-1, i.p. A dose of 300 mg kg-1 given 24 h after ischaemia also suppressed CA1 neuronal damage, but had no effect when given at 48 or 72 h. These results demonstrate a protective effect of orotic acid on ischaemic neuronal damage with a wide therapeutic time window.

Animals↗

PubMed1982

Effect of orotic acid on the excitability processes in central nervous system and on cerebral circulation in cats.

The influence of orotic acid on cortical excitability processes and cerebral circulation was studied in acute experiments in cats. The effect on CNS excitability was assessed by examination of the cortical visual-evoked potentials and the recovery cycles. The flash-evoked responses were recorded from visual cortex (VC), associative cortex (AsC) and auditory cortex (AuC). The recovery cycles were determined as the ratio of the average response to the test stimulus and those to the conditioning stimulus depending on the interstimulus interval duration. For investigation of cerebral circulation the method of local cerebral rheoencephalography (REG) was used. The following REG parameters were assessed: amplitude, anacrotic sections of the curve and its relative part, and duration of the wave. The arterial blood pressure was monitored continuously. Orotic acid administration (50 mg/kg i.v.) induced a significant increase in the amplitude of the primary response from VC and AsC. Significant shortening of the peak latency of the second wave of the response in the VC was also observed. The recovery cycles examination showed a facilitation of the test response. The changes observed indicate an increase of excitability processes in the CNS. The REG changes after orotic acid indicate a cerebrovascular resistance decrease and increase in cerebral blood volume. It is assumed that increased cortical activity by orotic acid may lead to an improvement of cerebral circulation.

Animals↗

PubMed2001

Orotic acid added to casein, but not to egg protein, soy protein, or wheat gluten diets increases 1,2-diacylglycerol levels and lowers superoxide dismutase activities in rat liver.

Effects of the dietary addition of orotic acid to a diet containing casein as a sole protein source on lipid levels in the liver and serum, activities of antioxidant enzymes in the liver, and some enzyme activities in serum, were compared with other diets containing egg protein, soy protein, or wheat gluten, respectively. 1. The contents in the liver of each lipid were increased by the addition of orotic acid as compared with those values without it. The orotic acid added to the casein diet caused accumulation of more liver total lipids, triacylglycerol, 1,2-diacylglycerol, and phospholipids than those fed three other diets. 2. The addition of orotic acid to the casein, but not to the other three diets, lowered the activities of liver superoxide dismutase and increased the activities of both serum ornithine carbamoyltransferase and alanine aminotransferase. Thus, the significant increase in serum ornithine carbamoyltransferase activities as the marker of liver lesions may result from the marked accumulation of liver lipids, decreased activities of hepatic superoxide dismutase, and the increased level of hepatic 1,2-diacylglycerol, followed by possibly the increased level of superoxide anion and increased activity of protein kinase C in rats fed the casein diet with orotic acid added.

Alanine Transaminase↗

PubMed1990

Lack of DNA alterations induced by orotic acid in rat liver as evaluated with two DNA unwinding methods.

One percent orotic acid supplemented diet is a promoting treatment in the rat model of liver carcinogenesis. After treatment with this type of diet, DNA alterations were observed using alkaline sucrose gradients and alkaline elution methods. In this work we have utilized two unwinding methods for the detection of DNA fragmentation. One method is a viscosimetric method in which the rate of increase in DNA viscosity with time is related to the rate of alkaline DNA unwinding. The second method measures fluorimetrically the amount of renatured and denatured DNA after different times allowed for alkaline DNA unwinding. These two methods are very sensitive in detecting DNA breaks induced by typical alkylating agents, X-rays and H2O2. The two unwinding methods were clearly negative for the orotic acid supplemented diet. We suggest that the DNA alterations detected with alkaline sucrose gradients and alkaline elution methods, after promoting treatment with orotic acid, are probably different from the DNA breaks induced by typical alkylating agents, X-rays and H2O2.

Animals↗

PubMed1983

Dietary orotic acid enhances the incidence of gamma-glutamyltransferase positive foci in rat liver induced by chemical carcinogens.

Feeding male Fischer F-344 rats for 5 weeks a diet containing 1% orotic acid, a precursor for pyrimidine nucleotide biosynthesis, resulted in an increased incidence of gamma-glutamyltransferase (EC 2.3.2.2) positive foci induced by chemical carcinogens including 1,2-dimethylhydrazine, diethylnitrosamine, benzo[a]pyrene, and aflatoxin B1. This unique effect of orotic acid can be accentuated by supplying a liver cell proliferative stimulus. The enzyme altered hepatocytes have a higher labelling index (4.4%) compared with that of the hepatocytes in the surrounding liver (0.26%). The effect of orotic acid on the increased incidence of foci cannot be attributed to either the induction of liver cell proliferation or the imposition of a preferential inhibitory effect on the proliferation of normal hepatocytes while permitting the carcinogen-modified hepatocytes to respond to an endogenous or exogenous liver cell proliferative stimulus and grow to form foci. Orotic acid also did not behave like some of the promoters of liver carcinogenesis such as phenobarbital and polychlorinated biphenyls in that it did not induce either the phase I or phase II components of hepatic drug metabolizing enzyme systems. Some of the possible mechanisms by which orotic acid enhances the incidence of gamma-glutamyltransferase positive foci by carcinogens are discussed.

Acyltransferases↗

PubMed2002

Effects of fatty liver induced by niacin-free diet with orotic acid on the metabolism of tryptophan to niacin in rats.

The effects of dietary orotic acid on the metabolism of tryptophan to niacin in weaning rats was investigated. The rats were fed with a niacin-free, 20% casein diet containing 0% (control diet) or 1% orotic acid diet (test diet) for 29 d. Retardation of growth, development of fatty liver, and enlargement of liver were observed in the test group in comparison with the control group. The concentrations of NAD and NADP in liver significantly decreased, while these in blood did not decrease compared to the control group. The formation of the upper metabolites of tryptophan to niacin such as anthranilic acid, kynurenic acid, and 3-hydroxyanthranilic acid were not affected, but the quinolinic acid and beyond, such as nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, were significantly reduced by the administration of orotic acid. Therefore, the conversion ratio of tryptophan to niacin significantly decreased in the test group in comparison with the control group.

Animals↗

PubMed1982

[Incorporation of orotic acid in myocardial uridine nucleotides: effect of isoproterenol and ribose].

1. The efficiency of the terminal steps of de novo synthesis of pyrimidine nucleotides in the myocardium was investigated by means of labelled orotic acid. [5-3H] or [6-14C] orotic acid was injected intravenously into rats. One hour later, the animals were sacrificed and the radioactivity incorporated into uracil nucleotides was determined on the compounds separated by HPLC. 2. The results showed poor orotic acid conversion into cardiac uracil nucleotides. The observation that administration of ribose to rats increases the incorporation of the labelled precursor is consistent with the hypothesis that de novo synthesis might be limited by the availability of phosphoribosyl-pyrophosphate. 3. The treatment of animals by isoproterenol (5 mg . kg-1 body weight s.c.) 5 h prior to the injection of the tracer, which gave rise to an expansion of the uridine nucleotide pool, did not result in an increase in the incorporation of labelled orotic acid. 4. From these preliminary results it may be assumed that "salvage pathways" play a predominant role in the regulation of the level of uracil nucleotides in the heart.

Animals↗