The incorporation of radioactive orotic acid into the nucleic acid pyrimidines of animal and human tumors.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “OROTIC ACID”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Species comparison of the influence of ammonia on orotic acid and urea biosynthesis in liver.
Although orotic aciduria occurs in both male and female rats fed an arginine-deficient diet, only hepatocytes from male rats exhibited an enhanced rate of orotate biosynthesis to increasing ammonium compared to controls. Inhibition of incorporation [14C]NaHCO3 into urea by norvaline in the rat and mouse was accompanied by a 20 and 25% increase in orotate biosynthesis, respectively. Injection of ammonium chloride (2 mmol/kg) or consumption of a diet devoid of arginine resulted in an increased urinary orotate excretion in the rat. Injection of a similar quantity of ammonium chloride in mice did not result in an orotic aciduria. The influence of ammonia and arginine on the biosynthesis of orotic acid and urea in isolated liver slices from various mammals was also examined. In rat, mouse and pig liver, increasing quantities of ammonia stimulated the incorporation of [14C]NaHCO3 into orotic acid. In porcine, bovine and ovine liver the incorporation of [14C]NaHCO3 into orotic acid was low and was minimally effected by supplemental ammonia. Addition of arginine to the incubation medium diminished the incorporation of [14C]NaHCO3 into orotic acid in the liver of all species examined except the cow and sheep. This decrease was accompanied by a stimulation of urea biosynthesis in the rat, but a depression in the pig. Addition of ammonium (5.0 mM) markedly increased the incorporation of [14C]NaHCO3 into urea in all mammalian liver slices examined. These studies show that the liver of various mammals can respond to increasing ammonia by increasing orotic acid biosynthesis. However, species differences in the response to ammonia are evident.
Ammonia↗
Neuroprotective effect of YM-39558, orotic acid ethylester, in gerbil forebrain ischemia.
We studied the effects of orotic acid and YM-39558 (2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid ethyl ester), orotic acid ethylester, on delayed neuronal death of hippocampal CA1 neurons induced by transient forebrain ischemia. Our data indicated that YM-39558 had high permeability across the blood brain barrier and was hydrolyzed to orotic acid, the active substance, in the brain. The neuronal damage was reduced significantly in animals intraperitoneally treated with YM-39558 (100 mg/kg x 3) after ischemia, but not with orotic acid in the same way. The results also suggested that the maintenance of a few ten micromolar orotic acid in cerebrospinal fluid were needed for its neuroprotective effects.
Animals↗
Orotic acid improves left ventricular recovery four days after heterotopic transplantation.
Orotic acid accelerates compensatory myocardial hypertrophy after regional ischemia and improves left ventricular function acutely after global ischemia. In this study, the effect of orotic acid on left ventricular function was investigated 4 days after global ischemia (75 minutes, 21 degrees C) using heterotopically transplanted rabbit hearts (n = 18). Experimental animals received daily 100-mg/kg doses of intraperitoneally administered orotic acid, starting 1 day before transplantation, and showed a threefold increase in the serum level of orotic acid by 4 days. After 1 hour of reperfusion, the developed pressure was equally depressed in both the control and experimental groups; however, 4 days later, the developed pressure in control animals was decreased by 3 +/- 3 mm Hg (versus the developed pressure measured at 1 hour) while the developed pressure in experimental animals was significantly increased by 25 +/- 8 mm Hg. Heterotopically transplanted hearts manifested diminished systolic function (stemming from ischemia and unloading) as well as decreased expression of adult myosin. Because orotic acid has been observed to produce an increase in protein synthesis in other models, we investigated whether this improvement in systolic function resulted from an orotic acid-mediated augmentation (or preservation) or normal adult myosin expression. Both orotic acid-treated and untreated hearts manifested decreased expression of the beta-myosin heavy chain protein and steady-state messenger RNA levels. Because function improved with decreased beta-myosin heavy chain expression, an alternate mechanism underlying orotic acid-mediated improvement in function is implicated. Nevertheless, orotic acid may be a therapeutic agent facilitating long-term recovery from global ischemia.
Animals↗
The urinary excretion of orotic acid and orotidine, measured by an isotope dilution assay.
Unknown concentrations of orotic acid can be measured by competition with a known amount of [carboxyl-14C]orotic acid for reaction with a limiting amount of phosphoribosylpyrophosphate in the presence of orotate phosphoribosyltransferase and orotidine monophosphate decarboxylase. The dilution of the specific radioactivity in the product 14CO2 is a sensitive and accurate measure of the amount of orotic acid present in the sample. Orotidine can also be determined after hydrolytic cleavage to orotic acid. The method was used to measure orotic acid and orotidine in urine samples from newborns, healthy controls and patients with gout or deficiency of hypoxanthine-guanine phosphoribosyltransferase receiving allopurinol. Urinary excretion of orotic acid and orotidine in newborns was similar whether the infants were breast-fed or received milk powder. The excretion of orotidine was increased in all patients receiving allopurinol. After allopurinol administration orotic acid excretion was increased in gouty patients but close to normal values in patients with deficiency of hypoxanthine-guanine phosphoribosyltransferase. The results are discussed in relation to the mechanism by which allopurinol inhibits pyrimidine metabolism.
Adolescent↗
[INFLUENCE OF INOSINIC ACID, ALONE OR COMBINED WITH OROTIC ACID, ON THE FREE NUCLEOTIDES IN THE RAT LIVER DURING CARBON TETRACHLORIDE POISONING].
Explore the source record for details and available documents.
Carbon Tetrachloride Poisoning↗
[3H]Formate incorporation into liver nucleic acids of chick. Relationships between orotic acid and vitamin B12.
Explore the source record for details and available documents.
Animals↗
Orotic acid sodium salt in kidney stones and urinary deposits.
Kidney stones from a plaice, Pleuronectes platessa, have been shown to consist of the sodium salt of orotic acid. Precipitation of orotic acid in human kidneys and urine samples has previously been reported but the precipitates must have been salts, most likely the sodium salt, of orotic acid and not the free acid. This reinterpretation is based on the acid strength of orotic acid and on data for the solubilities of sodium orotate and orotic acid. Sodium orotate is therefore a member on the list of compounds present in human urinary deposits and calculi. X-ray powder diagrams and d-values and IR-spectra of the sodium salt are recorded to facilitate future identifications.
Animals↗
Plasma urea-cycle-related amino acids, ammonium levels, and urinary orotic acid excretion in short-bowel patients managed with an oral diet.
BACKGROUND AND AIMS: The small intestine contains several enzymes involved in arginine synthesis and converts glutamine to citrulline, the major compound for endogenous arginine synthesis. This study was conducted to assess the plasma status of urea-cycle intermediates and orotic urinary excretion in short-bowel patients. METHODS: Thirteen stable short-bowel syndrome patients (7 men; 60.2+/-15.2 years) were studied. Patients were divided into moderately resected (Group A; n=6) and severely resected (Group B; n=7) according to their remnant bowel length (Group A: 61-150 cm; Group B: < or =60 cm). All subjects were consuming an oral diet plus dietetic supplements. Plasma urea-cycle amino acids, ammonium and urinary orotic acid were determined. RESULTS: Plasma glutamine levels were significantly higher in both patient groups than in the control group (P<0.001). Regarding citrulline, Group B levels were significantly lower vs. controls (P<0.001). Comparisons between patient groups showed higher arginine in Group A (P<0.05) and non-statistically lower citrulline in Group B. Blood ammonium and orotic urinary excretion were normal. CONCLUSIONS: Although plasma citrulline and glutamine alterations were found, patients showed no hyperammonemia or orotic aciduria, which suggests a certain degree of adaptation in arginine and related amino acid metabolism, when an adequate dietary supply of arginine is provided.
Adult↗
Urinary orotic acid excretion in sheep: effects of nitrogen, glucose and arginine.
The urinary excretion of orotic acid was investigated in four sheep. Nitrogen and energy intake were varied by infusions of urea and glucose. The effect of arginine infusion was also investigated. Nitrogen intake of 10.4 g/d led to a urinary excretion of orotic acid of 357 +/- 61 micrograms/d. Increasing N intake to 21.4 g/d significantly increased urinary orotic acid excretion to 747 +/- 46 micrograms/d. Glucose infusion (300 g/d) significantly decreased orotic acid excretion when N intake was 10.4 g/d, whereas arginine infusion (2.3 g/d) did not alter the excretion of orotic acid under these conditions. When arginine was infused at higher N intake (21.4 g/d), orotic acid excretion decreased from 822 +/- 74 to 624 +/- 46 micrograms/d. It is concluded that increasing N intake is accompanied by an enhanced urinary excretion of orotic acid. This excretion of orotic acid is significantly modified by glucose or arginine.
Abomasum↗
Alterations of cytoplasmic enzyme activities of liver in rats fed on diets containing orotic acid with dietary fibers.
1. Rats were fed with diets containing orotic acid with dietary fibers to induce alteration of lipid metabolism and cytoplasmic enzyme activities in the livers. Concentrations of blood glucose, serum insulin and free fatty acids (FFA) were measured. 2. In CP (cellulose + orotic acid) group compared to basal (cellulose - orotic acid) or CBH (corn bran hemicellulose + cellulose + orotic acid) groups, glucose-6-phosphate dehydrogenase, pyruvate kinase and ATP citrate lyase activities and FFA concentration were decreased according to lipid accumulation of livers. 3. In the CBH group, glycerokinase activity was higher than basal group.
Animals↗
Improvement of shuttle-box avoidance by combinations of orotic acid and central stimulants.
The effect of orotic acid and central stimulants on retention of shuttle-box avoidance was investigated in rats. Orotic acid (100 mg/kg) was injected 30 min before training; caffeine (20mg/kg), strychnine (1 mg/kg), or methylphenidate (10 mg/kg) were injected immediately after training. When given alone, these drugs improved avoidance retention when tested 24 h after training. However, improvement of retention was much more evident when orotic acid was given in combination with a stimulant. The data are discussed in relation to the role of macromolecule synthesis and arousal in memory formation.
Animals↗
[Influence of orotic acid on the enzymatic system activating amino acids].
Explore the source record for details and available documents.
Amino Acids↗
Variability of orotic acid concentration in cow's milk.
The average concentration of orotic acid in the milk of 412 Black and White bred cows from four Polish provinces was 0.618 +/- 0.233 mmol/l. There was no correlation between milk yield and concentration of orotic acid. A higher concentration of this pyrimidine in younger cows, and its increase during development of lactation was noted. The yearly pattern of orotic acid in milk and urine of four low-, and four high-orotate cows was examined. In spite of high average differences in milk orotate (0.397 and 0.813 mmol/l) no significant differences in urinary orotate (20.96 and 21.90 mumol/mmol creatinine) were observed. In both groups the lowest milk orotate level occurred in early lactation. The orotic acid content (mmol/l) in commercial milk products was as follows: skim milk--0.783; evaporated milk--0.538; cream 12% fat--0.367; buttermilk--0.449; yogurt--0.331; kefir--0.341; sour milk 2% fat--0.360; dried skim milk--1.042; Bebiko I (infant formula)--0.650. Leukemia led to the elevation (0.845 mmol/l), whereas mastitis to the depression (0.124 mmol/l) of milk orotic acid level.
Animals↗
Enhancement of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine-induced tumorigenesis in Sprague-Dawley rats by orotic acid.
The effect of orotic acid (OA) on the carcinogenicity of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) in rats was evaluated. A group of 5 week old Sprague-Dawley male rats were placed on a synthetic 20% protein diet containing 1% OA. A second group was placed on a regular, OA-free diet of similar composition. Approximately 2 weeks later, animals from both groups grown to 100 g were treated with 400 mg/kg HPOP delivered continuously for 14 days via 2002 Alzet osmotic pumps implanted s.c. Rats fed the OA diet were kept under this diet for 13 weeks following initiation of HPOP treatment and subsequently were placed on the regular diet for another 12 weeks, at which time they were killed. In the absence of OA, HPOP-treated rats developed adenomas in the kidney and lungs at incidences of 5 and 33% respectively, while pancreas and liver were unaffected. On the other hand, rats fed the OA diet and treated with HPOP developed renal mesenchymal tumors and pulmonary adenomas at incidences of 70 and 65% respectively. In addition, HPOP induced cystic lesions in the pancreas of animals fed the OA diet. The enhancement of the tumorigenic effectiveness of HPOP was at least partly ascribed to the effect of OA treatment on the rate by which carcinogen-induced alkylation of DNA was repaired in various tissues. Accumulation of N7-methylguanine in kidney, lung and pancreas of rats fed the OA diet was 1.6, 1.9 and 2.4 times higher than in respective organs of animals fed the regular diet. Similarly, concentrations of the premutagenic O6-methylguanine (O6-MeG) were 3.0, 3.1 and 2 times greater in the kidney, lung and pancreas of rats fed the OA diet than in the respective organs of those fed the regular diet. Feeding an OA diet to HPOP-treated rats did not have an effect on either the resistance of the liver to this carcinogen or on the level of O6-MeG accumulation in the DNA of this tissue.
Animals↗
Mechanism of cardioprotective effect of orotic acid.
The pyrimidine base, orotic acid (OA), markedly improves the function of recently infarcted hearts subjected to global ischemia. The mechanism of cardiac action of OA is unclear, but it has been proposed that OA acts by correcting a relative deficiency of nucleotide precursors required for RNA synthesis in the stressed myocardium or by improving myocardial energy supply. The aim of this study was to investigate the mechanism of action of OA by (1) determining whether a high dose of OA can raise the concentration of pyrimidine metabolites in plasma, liver, and heart; (2) examining the effects of OA on adenine nucleotide (AN) concentrations in normal and infarcted hearts, before and after global ischemia; and (3) determining the effect of uridine, an important metabolite of OA, on myocardial energy metabolism. Three studies were performed: (1) The time course of changes in tissue and plasma concentrations of pyrimidine compounds was examined in unoperated rats after the administration of 100 mg/kg OA. (2) Rats were given OA (30 mg/kg/d) for 2 days after experimental infarction, and tissue and plasma pyrimidine concentrations were examined; the hearts were removed for perfusion in the isolated working rat heart model (37 degrees C), subjected to 30 minutes of global ischemia, and recovery of function was assessed. AN content was assessed in the noninfarcted myocardium before and after ischemia. Isolated hearts were subjected to 30 minutes of hypoxic perfusion and the effect of adding 17 microM uridine to the perfusate was examined. Study 1 showed that OA administration produced an increase in hepatic uridine and cytidine, followed by increased plasma uridine and cytidine (cytidine, +55%, P < 0.001; uridine, +124%, P = 0.011). Myocardial uracil nucleotides increased temporarily after 4 hours (+21%, P < 0.01). In infarcted hearts after 2 days of OA administration, there were no significant changes in myocardial uracil or cytosine nucleotides or total RNA. Infarction significantly reduced functional recovery after global ischemia (sham = 62%; infarct = 26% of preischemic level; P < 0.05). OA improved the recovery of preischemic function by 133% (P < 0.05) in infarcted, but not sham-operated, hearts. Preischemic ATP and total adenine nucleotides (TAN) were decreased in the surviving myocardium of infarcted hearts (ATP reduced from 21.7 +/- 0.8 to 14.7 +/- 0.7 mumol/g dry wt, P < 0.001; TAN decreased from 30.3 +/- 0.8 to 22.4 +/- 1.1 mumol/g dry wt, P < 0.001). OA treatment prevented these reductions. Study 3 showed that uridine improved myocardial ATP and TAN levels, and decreased purine loss in hypoxic hearts. The increased AN levels were accompanied by evidence of enhancement of anerobic glycolysis. We conclude: (1) That OA acts on the heart via the liver by increasing the availability of plasma uridine and cytidine. (2) Uridine is capable of increasing myocardial ATP production by stimulating anerobic glycolysis. (3) OA treatment improves tolerance to global ischemia in infarcted but not normal hearts by preventing depletion of AN in the surviving myocardium.
Adenine Nucleotides↗
Utilization of labelled uridine, cytidine and orotic acid for determination of ribonucleic acid synthesis in mouse liver.
[3H]uridine and [3H]orotic acid were equally utilized for labelling of RNA in mouse liver. Incorporation of [3H]cytidine was 2-3 times as high as that of [3H]-labelled uridine or orotic acid. These results differ from findings in rat liver, where both cytidine and orotic acid are better utilized for RNA labelling than is uridine. The ratio between liver RNA [3H]-activity and volatile [3H]-activity was 2, 3 and 13, respectively, at 300 min after injection of labelled uridine, orotic acid and cytidine, indicating an efficient chanelling of cytidine into liver anabolic pathways.
Animals↗
Orotic acid in guinea pig milk: changes in concentration during lactation.
The orotic acid concentration in guinea pig milk decreased rectilinearly beginning on d 1 through a lactation duration of 21 d. Concentration was 29 micrograms/ml on d 1 and 5 micrograms/ml on d 17. On d 18 to 21 it was less than 1 microgram/ml. The regression equation of orotic acid on day of lactation was: Y(micrograms orotic acid per milliliter milk) equals 32.3 - 1.6X (day of lactation) with a correlation coefficient of .94. Total orotic acid on a daily basis peaked on d 6 at 950 micrograms and declined to less than 5 micrograms by d 21. The rectilinear regression equation from d 6 to 21 was as follows: Y(micrograms orotic acid per milliliter milk) equals -1.64 + .68X (grams of milk production per day) with a correlation coefficient of .97. This may be used as a marker for persistency of lactation.
Animals↗