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PubMed2000

Vibrational analysis and spectra of orotic acid.

The IR and Raman spectra of polycrystalline anhydrous orotic acid and its N1, N3, and O12 trideuterated isotopomer are recorded in the 4000-40 cm(-1) spectral interval as part of a series of vibrational analyses of nucleosides, nucleotides, and related compounds carried out in our laboratory. The frequencies of the fundamental transitions and the potential energy distributions of the 39 normal modes of orotic acid and its isotopomer are calculated by an ab initio density functional theory Becke3P86/6-311G** treatment. Assignments of the vibrational modes are proposed that consider the results of these calculations and the observed spectra. The results of the ab initio treatment are related to crystallographic and spectral data, and they are compared with previous assignments for similar molecules.

Deuterium↗
PubMed1986

The orotic acid concentration in the blood, milk, and urine of dairy cows fed with urea supplemented diet.

The experiment was performed on 4 cows Black and White, 550-650 kg of body weight, before and during 100 days after parturition. Two cows were fed with control and the next two with urea supplemented diet (urea-N constituting about 20% of total N in ration, 13% c.p. in DM). In cows fed with urea supplemented diet the considerable but unequal increase of urinary orotic acid excretion (particularly evident in first 30 days of lactation) was observed. There was however no influence of urea ration on the level of orotic acid in milk. The average orotic acid level in blood plasma (1.14 +/- 0.71 mumol X l-1 and 0.94 +/- 0.22 mumol X l-1 for control and urea fed cow respectively) established 0.01 and 0.001 of the average orotic acid concentration in urine and milk, respectively. Feeding with urea ration did not affect the level of orotic and UMP but increased the uridine concentration in blood plasma. During the parturition the lowest level of orotic acid in blood plasma, milk and urine was observed.

Animal Feed↗
PubMed1981

Influence of combined application of orotic acid and central stimulants on memory processes and participation of cholinergic mechanisms.

Experiments on albino rats trained and tested for memory in a maze have shown the following. Orotic acid (100 mg/kg) does not influence learning, but it improves retention. On the background of orotic acid the central stimulants caffeine, strychnine and amphetamine do not change their learning-facilitating effect. Combined application of orotic acid and stimulants, however, has a stronger effect on retention than their independent application. The increased retention-improving effect of the combination of orotic acid and central stimulants disappears after blocking of the central M-cholinergic structures with atropine. The results obtained are interpreted in the light of the views of the role of the excitation level after training for the course of the biosynthetic processes in the memory-facilitating effect of the central stimulants.

Amphetamine↗
PubMed1999

Effects of oral administration of orotic acid on hepatic morphologic characteristics and serum biochemical variables in cats.

OBJECTIVE: To evaluate orotic acid (OA) as a possible etiologic factor in cats with idiopathic hepatic lipidosis (HL). ANIMALS: 20 clinically normal adult female cats. PROCEDURE: Cats were fed a control diet or a diet containing less protein. On day 1 of the control period, blood, urine, and liver biopsy specimens were obtained. Each cat was given an oral dose of water daily. On days 8, 15, and 22, blood and urine specimens were collected as on day 1. On day 29, liver, blood, and urine samples were obtained as on day 1. After a resting period of 30 to 60 days, cats were treated with orotic acid. Serum biochemical analyses, urinary OA-to-creatinine ratios, and liver biopsy specimens were evaluated. Cats were given OA orally (suspension or capsules) for 29 days. Sample collection and data obtained were identical to those described for the control period. RESULTS: Urinary OA-to-creatinine ratios were significantly higher in all treated cats, but ratios were significantly higher in those receiving OA in capsules than in those receiving OA in suspension. Diet or treatment did not alter hepatic biochemical or histologic variables significantly. However, 7 cats given the highest dose of OA in capsules developed azotemia, urolithiasis, and renal changes. CONCLUSIONS: Most concentrations of OA used in this study did not induce HL in cats during a 29-day period, but the highest dosage used did result in renal disease. CLINICAL RELEVANCE: Orotic acid does not appear to be involved in the genesis of HL in cats.

Administration, Oral↗
PubMed1987

Actions of dietary orotic acid on liver synthesis of phosphatidylcholine and phosphatidylethanolamine in rats.

The in vivo rates of the reactions of the cytidine pathways of liver phosphatidylcholine and phosphatidylethanolamine synthesis were measured in rats after 1 day of feeding on a semisynthetic diet containing 1% orotic acid. The calculations were made from the specific and total radioactivity versus time curves of the precursors and products following intraportal injection of [1,2-14C]choline, [2-14C]ethanolamine, and [2-3H]glycerol. The liver CTP level was increased twofold and the rates of CDP-choline and phosphatidylcholine synthesis were stimulated 4.5-fold in the rats fed orotic acid. The rate of CDP-ethanolamine synthesis was increased but could not be accurately quantified because of its extreme rapidity. No change occurred in the rate of the ethanolaminephosphotransferase reaction and the overall rate of phosphatidylethanolamine synthesis was unchanged by orotic acid feeding. The catalytic activities of the enzymes of the cytidine pathways of phosphatidylcholine and phosphatidylethanolamine synthesis were not affected by feeding orotic acid for 1 day. Similar findings were obtained 3 h following intragastric administration of 100 mg of orotic acid. The results suggest the possibility that changes in the levels of liver CTP may play a role in regulation of the cytidine pathway of liver phosphatidylcholine synthesis but not of phosphatidylethanolamine synthesis, because the latter pathway appears to be tightly controlled at the ethanolaminephosphotransferase step.

Animals↗
PubMed2004

Acetate-mediated production of orotic acid by ura3 mutants of Candida albicans.

Candida albicans ura3 mutants were found to produce large amounts of orotic acid when the growth medium was supplemented with sodium acetate. Experiments with 13C-labeled acetate showed that the acetate served as a precursor of orotic acid. This system of acetate-mediated production of orotic acid is similar to other documented microbial producers in yield but unique for its acetate requirement.

Acetates↗
PubMed1980

Diagnostic value of orotic acid excretion in heritable disorders of the urea cycle and in hyperammonemia due to organic acidurias.

Orotic acid excretion in urine in increased in ornithine transcarbamylase deficiency, citrullinemia and argininemia; it is barely increased in argininosuccinic aciduria and normal in carbamylphosphate synthetase deficiency and in hyperammonemia due to organic aciduria. The determination of orotic acid excretion is useful in differentiating the cases of hyperammonemia and reduces the need for enzymatic assays on tissue biopsies for decisions on therapy. The data indicate that orotic acid does not merely reflect ammonia concentration in plasma, but depends on carbamylphosphate concentration. Arginine could play a key role in the regulation of ammonia detoxication.

Amino Acid Metabolism, Inborn Errors↗
PubMed1982

Impaired glycosylation in liver microsomes of orotic-acid-fed rats.

In rats fed orotic acid, the incorporation in liver subcellular fractions of sugars injected intraperitonealy is altered only for mannose, but not for fucose or galactose. Direct determinations of several glycosyltransferases are done in smooth and rough microsomes: fucosyl-, glactosyl-, N-acetylglucosaminyltransferase activities are at quite similar levels in normal and fatty livers. By contrast, sialyltransferase activity is increased (+50%) in smooth microsomes of fatty livers, while mannosyltransferase activity is inhibited by 30%. These alterations are not caused by interfering reactions (pyrophosphatases or proteases). For the mannosyltransferase activity, the inhibition is found in the dolichylphosphorylmannose intermediates. Kinetic studies suggest that there is deficiency of both enzyme and endogenous dolichyl phosphate.

Animals↗
PubMed1990

Studies on the mitoinhibitory effect of orotic acid on hepatocytes in primary culture.

Orotic acid (OA), a promoter of liver carcinogenesis, inhibited proliferation of primary hepatocytes in culture as monitored by labelling index, mitotic index and total DNA content. The mitoinhibitory effect of OA was seen even in the presence of a strong mitogen such as epidermal growth factor (EGF). The growth inhibitory effect of OA was not due to cell killing. Upon exposure to OA the hepatocytes exhibited an increase in the ratio of uridine nucleotides to adenosine nucleotides, and as this ratio increased the response of hepatocytes to proliferate in the presence or absence of EGF decreased. Washing the hepatocytes free of added OA resulted in a gradual decrease in the ratio of uridine nucleotides to adenosine nucleotides, paralleled by an increase in hepatocytic proliferation. Adenine, an agent that inhibits the metabolism of OA to uridine nucleotides, not only inhibited the increase in the ratio of uridine nucleotides to adenosine nucleotides but also counteracted the OA-induced mitoinhibitory effect. These results, together with our earlier observations, suggest that an imbalance in nucleotide pools composed of an increase in uridine nucleotides and a decrease in adenosine nucleotides appears to be important for OA-induced mitoinhibition.

Animals↗
PubMed1984

Radioautographic visualization of differences in the pattern of [3H]uridine and [3H]orotic acid incorporation into the RNA of migrating columnar cells in the rat small intestine.

The epithelium of rat small intestine was radioautographed to examine whether RNA is synthesized by the salvage pathway as shown after [3H]uridine injection or by the de novo pathway as shown after [3H]orotic acid injection. The two modes of RNA synthesis were thus investigated during the migration of columnar cells from crypt base to villus top, and the rate of synthesis was assessed by counting silver grains over the nucleolus and nucleoplasm at six levels along the duodenal epithelium--that is, in the base, mid, and top regions of the crypts and in the base, mid, and top regions of the villi. Concomitant biochemical analyses established that, after injection of either [5-3H]uridine or [5-3H]orotic acid: (a) buffered glutaraldehyde fixative was as effective as perchloric acid or trichloracetic acid in insolubilizing the nucleic acids of rat small intestine; (b) a major fraction of the nucleic acid label was in RNA, that is, 91% after [3H]uridine and 72% after [3H]orotic acid, with the rest in DNA; and (c) a substantial fraction of the RNA label was in poly A+ RNA (presumed to be messenger RNA). In radioautographs of duodenum prepared after [3H] uridine injection, the count of silver grains was high over nucleolus and nucleoplasm in crypt base cells and gradually decreased at the upper levels up to the villus base. In the rest of the villus, the grain count over the nucleolus was negligible, while over the nucleoplasm it was low but significant. After [3H]-orotic acid injection, the number of silver grains over the nucleolus was negligible at all levels, whereas over the nucleoplasm the number was low in crypt cells, but high in villus cells with a peak in mid villus. The interpretation is that, except for a small amount of label incorporated into DNA from either precursor by crypt cells, the bulk of the label is incorporated into RNA as follows. In the crypts, cells make almost exclusive use of uridine, that is, of the salvage pathway, for the synthesis of ribosomal RNA in the nucleolus and of messenger and transfer RNA in the nucleoplasm. However, when cells pass from crypt to villus, they mainly utilize orotic acid--i.e., the de novo pathway--for the synthesis of messenger and transfer RNA within the nucleoplasm.

Animals↗
PubMed1979

Urinary excretion of orotic acid, orotidine and other pyrimidines in a patient with purine nucleoside phosphorylase deficiency.

Urinary orotidine and orotic acid have been determined in a patient with purine nucleoside phosphorylase (PNP) deficiency under various dietary therapeutic conditions. For this purpose a new procedure for the analysis of both compounds has been developed, consisting of prefractionation with Dowex 1X8, followed by two HPLC steps on a micro Bondapak NH2 and a micro Bondapak C18 column. With this method normal as well as slightly elevated excretions of orotic acid have been found in our patient. No evidence was obtained for inhibition of OPRT by purine (deoxy)nucleosides as a cause of pyrimidine starvation. A significant increase of urinary orotidine was found after loading with allopurinol. For comparison excretory values in a patient with ornithine transcarbamylase deficiency and also in a patient with orotic aciduria type I are shown. The possible cause of the slight increase in urinary orotic acid in our patient has been discussed.

Allopurinol↗
PubMed1991

The effect of orotic acid on the response of the recently infarcted rat heart to hypothermic cardioplegia.

Patients with a recent myocardial infarction have a higher morbidity and mortality than comparable patients with chronic myocardial ischaemia. We postulated that this might be due to a reduced overall tolerance of the heart to cardioplegic arrest in the presence of a recent infarct. We postulated that orotic acid, a pyrimidine precursor which augments the rate of protein synthesis, might improve the response of the recently infarcted heart to cardioplegic arrest. Myocardial infarction was produced in rats by coronary ligation. The rats were then divided into two groups according to whether they were treated with oral orotic acid (10 mg/kg per day) or untreated. A sham-operated (non-infarcted) group served as normal controls. After 2 days, the hearts (n = 12 per group) underwent 1 h of cardioplegic arrest at 23 degrees C on the isolated working heart apparatus. Before arrest, maximum cardiac function in the untreated infarct group was lower than in the normal group (P less than 0.05), whereas in the treated group, function was similar to the normal group. After arrest there was severe depression of cardiac function in the untreated infarct group: only 57% recovery of the pre-arrest value compared with 86% in the normal group (P less than 0.001). In the orotic acid treated group, recovery (90%) was significantly greater than in the untreated group (P less than 0.001) and equivalent to the normal group. Oxygen utilisation, when corrected for external work, was higher in both infarct groups than in the normal group before and after arrest (P less than 0.05 in both cases). Total uridine nucleotide content of the infarcted and non-infarcted zones of the heart was increased. Treatment with orotic acid produced a further upward trend in uridine nucleotide levels. We conclude that an established, recent infarct reduces the overall tolerance of the heart to hypothermic cardioplegia. Treatment with orotic acid improves the function of the infarcted heart following cardioplegic arrest, and may therefore improve the results of urgent cardiac surgery in patients with myocardial infarction.

Animals↗
PubMed1987

Radioautographic comparison of RNA synthesis patterns in the epithelial cells of mouse pyloric antrum following 3H-uridine and 3H-orotic acid injections.

RNA synthesis was examined in the epithelial cells of the mouse pyloric antrum using radioautography 20 min after injection of either 3H-uridine or 3H-orotic acid. The epithelium of the mouse antrum was known to invaginate into blind tubular units composed of mucous cells arranged from base to top into a gland, an isthmus, and a pit. These were subdivided into segments and, after radioautography, silver grains were counted over cell nuclei in each segment. Following 3H-uridine injection, silver grains were present over all nuclei but were more abundant over those of the isthmus than of the gland or the pit. When nuclei were examined in the electron microscope, nucleoplasmic as well as nucleolar silver grains were more numerous in the isthmus than in the pit or gland. Following 3H-orotic acid injection, silver grains were again present over all nuclei; but maximal incorporation appeared to be in pit cell nuclei where, by electron microscopy, it was mainly assigned to the nucleoplasm. When the incorporation was calculated per whole nucleus, however, it was less in pit cell than in isthmal cell nuclei. Even so, the proportion of label in pit cell nuclei was much greater than after 3H-uridine injection. The interpretation of these findings is based on the fact that isthmal cells are immature, whereas cells migrating from the isthmus to become gland or pit cells show increasing differentiation. The immature cells of the isthmus incorporate both uridine and orotic acid more effectively than do the differentiated cells of pit and gland. Since silver grain counts over nuclei provide an index of the rate of RNA synthesis, this synthesis proceeds more actively in the isthmus than in the pit or gland. This is true of ribosomal RNA synthesis, as shown by nucleolar grain counts, and of other RNA's synthesis, as shown by nucleoplasmic grain counts. It seems, however, that while uridine is involved in the synthesis of all types of RNA, orotic acid is mainly implicated in the synthesis of the heterogeneous RNA from which the messenger RNA arises.

Animals↗
PubMed1992

Elevated urinary excretion of orotic acid in sheep caused by intraruminal infusion of sodium propionate.

1. The effect of sodium propionate on urinary excretion of orotic acid was investigated. 2. Solutions containing sodium propionate or NaCl, 750 mM/day each, were continuously infused into the rumen for 10 days. 3. During NaCl infusion, an urinary orotic acid excretion of 290 +/- 80 micrograms/day was noted. The intraruminal infusion of sodium propionate raised the concentration of propionic acid in the rumen fluid from 14.0 +/- 0.9 to 26.9 +/- 1.9 mM. 4. During this experimental period the excretion of orotic acid via urine significantly increased to 492 +/- 30 micrograms/day. Parameters of nitrogen balance were not altered by propionate. 5. It is suggested that the site of propionate action in intact sheep is in the pyrimidine synthesis pathway.

Animals↗
PubMed2000

Urinary orotic acid levels in normal pregnancy and pregnancy-induced hypertension.

Our objective was to study the urinary levels of orotic acid in normal pregnancy and in pregnancy-induced hypertension. Such levels were measured using high-performance liquid chromatography with column-switching. The levels of urinary orotic acid (micromol/g creatinine) in normal pregnancy (n = 14) were 6.9 +/- 2.3 (first trimester), 10.1 +/- 2.4 (20 weeks) and 12.0 +/- 3.7 (30 weeks). In pregnancy-induced hypertension (n = 14), the corresponding levels were 6.5 +/- 1.7, 7.8 +/- 2.7 and 7.6 +/- 2.3, respectively. Normal pregnant subjects individually showed a significant elevation at 20 and 30 weeks of gestation as compared with those in the first trimester (p < 0.01). A high consumption of arginine in nitric oxide production during normal pregnancy may cause a physiological elevation of urinary orotic acid. The absence of an elevation in pregnancy-induced hypertension may be associated with a decrease in nitric oxide production.

Arginine↗