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PubMed1986

Effect of hepatic artery ligation on the incorporation of 3H-orotic acid into an adenocarcinoma transplanted to rat liver.

In the model of secondary liver cancer in Wistar rats a study was made of the influence of hepatic artery ligation (HAL) on the amount of nucleotides and RNA in tumor and liver tissue and on the uptake of 3H-orotic acid into these compounds and DNA after labelling for 90 minutes. Ten days after inoculation with tumor cells into the central liver lobe, a catheter was placed into the portal vein in all rats and in half of them the hepatic artery was ligated. On days one, three, five or ten, rats were given 3H-orotic acid through the catheter. On day ten 3H-orotic acid was also infused via the femoral vein or intraperitoneally. After HAL there was a decrease in the nucleotide and RNA content of the tumor cells after one, three and five days. There was no such decrease in the liver cells. In all HAL rats there was an increase in the nucleotide and RNA content of the tumor cells at day ten compared to day five. The ratio of RNA to acid soluble fraction labelling in tumors was also increased on day ten in all groups compared to HAL rats at day five. The increased uptake of 3H-orotic acid into tumour RNA at day ten after HAL strongly suggests rearterialization. There was no support for an increased vascularization of the tumor from the portal vein on day three or five. In the liver tissue, HAL had no influence. This experimental study gives no support for the use of hepatic dearterialization followed by intraportal infusion av cytostatic agents in clinical settings.

Adenocarcinoma↗
PubMed1978

Lower gastric secretion and higher incorporation of orotic acid into liver RNA in rats treated with 5-azacytidine and cycloheximide.

Out of different azapyrimidines tested for their ability to affect metabolism of orotic acid in the liver of rats kept on food only 5-azacytidine resulted in the enhanced incorporation of orotate into liver RNA following 24 hr pretreatment. Similar effect was observed also in cycloheximide-treated animals. No stimulation of orotic acid utilization following 5-azacytidine or cycloheximidine treatment was observed in the liver of starved animals. Both drugs (but not other pyrimidine analogues tested) depressed markedly gastric secretion in rats and caused decreased evacuation of the stomach. The decreased secretion of pepsin and lower gastric acidity resulting in drug-simulated starvation of the treated animals are discussed in relation to the enhanced uptake of orotic acid into liver RNA.

Animals↗
PubMed2003

Concentration and purification of orotic acid directly from whey with an expanded bed adsorption system.

The development of an expanded bed process for the concentration and purification of orotic acid directly from whey is described. Different commercially available adsorbents were tested in series of pilot batch adsorption experiments to determine the most suitable separation system. Best results were achieved using a weak anion-exchange matrix. An elution protocol was established using MgCl2 as eluting agent to recover the adsorbed orotic acid with approximately 85% yield and 10-fold concentration. Purified orotic acid was precipitated under acid conditions with a yield of 95%.

Adsorption↗
PubMed1998

Effects of Triton WR 1339 and orotic acid on biliary and serum dolichols in rats.

Two lysosomal storage diseases, aspartylglucosaminuria and mannosidosis, are associated with highly elevated serum dolichol concentrations. To elucidate possible mechanisms leading to elevated serum dolichols, we studied the effects of Triton WR 1339 (known to increase serum cholesterol) and orotic acid (known to decrease serum cholesterol) on blood and biliary dolichol and beta-hexosaminidase levels in rats. In Triton WR 1339-treated rats, serum dolichol was markedly increased compared with saline-treated controls 1 (400 +/- 70 ng/mL, n = 7 v 85 +/- 11 ng/mL, n = 8, P < .001), 4 (789 +/- 70 ng/mL, n = 10 v 110 +/- 10 ng/mL, n = 7, P < .0001), and 8 (549 +/- 43 ng/mL, n = 8 v 87 +/- 8 ng/mL, n = 7, P < .001) days after administration of the drug. By contrast, serum dolichol was decreased (64 +/- 5 ng/mL, n = 8 v 119 +/- 7 ng/mL, n = 8, P < .0001) after a 7-day orotic acid feeding compared with controls. Serum beta-hexosaminidase was unaffected by both treatments. Orotic acid also increased biliary dolichol (280 +/- 47 ng/100 g body weight [BW]/h, n = 7 v 83 +/- 15 ng/100 g BW/h, n = 7, P < .01) and beta-hexosaminidase (21 +/- 3 mU/100 g BW/h, n = 7 v 8.3 +/- 2 mU/100 g BW/h, n = 9, P < .01) excretion compared with controls. Thus, both Triton WR 1339 and orotic acid have an effect on dolichol metabolism, and it is conceivable--based on our results--that serum dolichol concentrations are regulated, at least in part, by a mechanism similar to that for serum cholesterol levels.

Animals↗
PubMed1985

Orotic acid, a promoter of liver carcinogenesis induces DNA damage in rat liver.

Orotic acid, a precursor of pyrimidine nucleotide biosynthesis and a promoter for liver carcinogenesis, when fed at 1% level in a diet for 5 weeks resulted in liver DNA damage. The damage can be monitored as alkali-labile lesions using alkaline sucrose gradients as well as alkaline elution technique. Furthermore, the induced DNA damage persists for up to three weeks after withdrawal of the orotic acid diet. The fact that several skin-tumour promoters also induce DNA damage raises the question whether DNA damage is a component in tumour promotion.

Animals↗
PubMed1989

Orotic acid overproduction in experimental cirrhosis of rats.

Ammonia clearance, portal blood ammonia, and amino acid concentrations were studied during induction of cirrhosis by carbon tetrachloride in rats. Exposure to CCl4 vapors twice weekly for 7-16 weeks doubled orotic acid excretion. If exposure was discontinued for 7 days, the orotic acid excretion decreased despite the presence of cirrhosis proven histologically. Replacement of dietary casein with soybean protein eliminated the CCl4-induced orotic aciduria in growing rats but not in adults. Supplementation of casein with 1.5% arginine did not prevent CCl4-induced orotic aciduria. [14C]Orotate uptake into RNA and DNA of liver was not impaired. Perfusion of livers of cirrhotic animals with ammonia concentrations between 0.2 and 3.0 mM revealed no significant decreases in urea synthesis rates due to cirrhosis and no increase in the tendency to make orotic acid at a given ammonia concentration. However, ammonia uptake by cirrhotic livers was significantly reduced, resulting in higher ammonia concentrations in the effluent when there was moderate-to-severe cirrhosis. Portal blood samples taken from rats exposed to CCl4 had higher ammonia concentrations as cirrhosis worsened. The results lend support to the "intact hepatocyte" hypothesis of cirrhosis which attributes metabolic abnormalities to intrahepatic shunts.

Ammonia↗
PubMed1977

[Effect of oxytocin on regional 3H-orotic acid uptake in rat brain].

The uptake of the RNA precursor [3H] orotic acid by 18 brain regions of male rats was measured after intracarotid injection and a survival time of 15 s. Ocytocin added to the injected solutions (final concentrations: 1 to 1000 mU/ml) caused a dose-dependent enhancement of tracer uptake by 11 areas. Some of these regions (e.g. hippocampus) are thought to be involved in the behavioral effects of vasopressin and other peptide hormones (Van Wimersma Greidanus et al., 1975 a). Results of experiments in which the net uptake of tritiated water was used as a measure of relative blood flow led us to the conclusion that the blood-brain barrier permeability to [3H] orotic acid rather than the cerebral blood flow is changed by ocytocin. The present results support the assumption that the enhanced precursor supply caused by ocytocin might contribute to the influence of this peptide hormone on memory consolidation.

Animals↗
PubMed1988

Apolipoproteins of the orotic acid fatty liver: implications for the biogenesis of plasma lipoproteins.

Rats fed orotic acid develop fatty livers characterized by triglyceride-laden, membrane-bounded vesicles designated "liposomes." We have measured the levels of apolipoproteins in isolated liposomes and other subcellular fractions by SDS-polyacrylamide gel electrophoresis, electrotransfer, and immunodecoration. Apolipoproteins Bh, Bl, E, and C appear to cofractionate; for these proteins, the liposomal pool represents a large portion of their total intracellular mass. However, liposomes are deficient in both variants of apoB relative to apoE and apoC when compared with rat plasma very low density lipoprotein (VLDL). Albumin and apolipoproteins A-I and A-IV are also found in liposomes, but this organelle represents a minor fraction of their total intracellular mass. The liposomal apolipoproteins show varying degrees of association with cisternal lipid and with organelle membranes. Orotic acid may selectively block VLDL production at the level of particle assembly or transorganellar movement. We conclude that liposomal contents probably represent exaggerated accumulations of VLDL assembly intermediates, and that the intracellular partitioning of high density lipoprotein-destined from VLDL-destined components occurs at an early stage in particle biogenesis. Moreover, some unique structural feature of apoB may effect movement of VLDL assembly intermediates through secretory organelles.

Animals↗
PubMed1979

Interrelations between uptake of [14C]orotic acid and labeling of UTP and RNA in rat and mouse liver after partial hepatectomy.

The uptake and utilization of [6-14C]orotic acid for UTP and RNA synthesis were studied in rat and mouse liver at 24 h after partial hepatectomy. Rat liver concentrated radioactivity relative to blood several-fold better than did mouse liver after both sham-operation and partial hepatectomy. The results showed that in mouse liver, contrary to rat liver, the orotic acid uptake was not increased after the partial hepatectomy. In rat liver, the precursor uptake and the labeling of UTP increased by about 75% whereas the specific radioactivity of RNA increased 2 to 3-fold after the operation, thus indicating an increased RNA synthesis. Mouse liver showed no increased [14C]orotic acid uptake or labeling of UTP or RNA at 24 h after partial hepatectomy.

Animals↗
PubMed1991

Influence of orotic acid on performance, liver lipid content, and egg cholesterol level of laying hens.

Three experiments were conducted to determine the effects of dietary orotic acid (OA) on laying hen performance, liver lipid content, and plasma and egg cholesterol levels. Laying hens were fed a basal diet supplemented with 0, .5, 1.0, and 2.0% OA for 8 wk. Performance of the hens and cholesterol levels were measured at biweekly intervals. In all three experiments, OA decreased (P less than .05) BW in a linear manner. In two experiments, OA caused a linear decrease in total liver lipid (P less than .05), and in a third experiment OA resulted in a quadratic effect (P less than .01) on liver lipid content. There were no effects observed by OA supplementation on egg weight, yolk weight, percentage yolk, or egg production. Orotic acid failed to influence egg cholesterol content in any of the biweekly measurements of the three experiments. In two experiments, total plasma cholesterol content was not influenced by OA supplementation. Orotic acid significantly reduced (P less than .05) free and total plasma cholesterol in a third experiment when measured at Weeks 4, 6, and 8 of the experiment. The data indicate that OA is an ineffective dietary supplement for reducing egg cholesterol levels in laying hens.

Animals↗
PubMed2001

Capillary zone electrophoresis of orotic acid in urine with on-line isotachophoresis sample pretreatment and diode array detection.

Potentialities of capillary zone electrophoresis with on-line isotachophoresis sample pretreatment and diode array detection (ITP-CZE-DAD) to the separation, detection and identification of trace analytes present in biological matrices were investigated. Urine represented a multicomponent, variable and high ionic strength matrix while orotic acid was chosen as a model analyte of a practical clinical relevance in this investigation. Using the ITP-CZE combination in the column-coupling configuration of the separation system ITP provided an enhanced sample load capacity to the separation system (a 30 microl sample injection volume), concentrated the analyte and served as an on-line sample clean up technique. On the other hand, CZE performed a final separation of the analyte from matrix constituents present in the ITP pretreated sample and provided favorable conditions for its detection and identification by DAD. Using current correction and smoothing procedures analytically relevant DAD spectra of orotic acid could be obtained also in instances when this was injected in a model sample at a 2 x 10(-7) mol/l concentration (an estimated limit of determination of orotic acid at a 218 nm detection wavelength). ITP-CZE separations of urine samples (based on differences in acid-base properties and host-guest complexations of the analyte and matrix anionic constituents) led to significant sample clean ups. Consequently, DAD spectra of orotic acid matching its reference spectrum, could be acquired also in instances when the acid was present in urine matrices (loaded in 30 microl injection volumes of 20-fold diluted urine samples) at 4-6 x 10(-7) mol/l concentrations. Here, residual trace matrix interferents prevented a closer approach to the above value attainable for model samples. Although this work was focused only on one analyte and urine matrix it implies very promising potentialities of the ITP-CZE-DAD combination in the identification and quantitation of trace analytes present in biological matrices, in general.

Adult↗
PubMed1980

Possible significance of changes in the energy metabolism for the release of liver lactate dehydrogenase and for the uptake and incorporation of [14C]-orotic acid into liver ribonucleic acid after partial hepatectomy.

The mouse liver revealed no increased incorporation of [14C]-orotic acid into either the total acid-soluble fraction, the uridine triphosphate or the RNA at 6 and 24 h after partial hepatectomy. In regenerating mouse and rat liver, the concentration of adenosine triphosphate was decreased 15-20% at 6 h, but was in the same range as that of the controls at 24 h. The adenosine monophosphate concentration of mouse liver increased 4-fold and 2-fold at these times after partial hepatectomy, respectively. The results indicate no direct relationship between the energy metabolism and the uptake and incorporation of orotic acid into RNA of regenerating liver. The activity of mouse plasma lactate dehydrogenase 5 (LDH 5) was increased 12-fold at 6 h and 5-fold at 24 h after partial hepatectomy. In rat, the LDH 5 activity was increased 2-fold at 6 h but was not different from that of the controls at 24 h. An increased leakage of LDH 5, possibly related to the decreased energy content of the liver, was thus revealed by the partially hepatectomized mice.

Adenine Nucleotides↗
PubMed1992

Assessment of the capabilities of capillary zone electrophoresis for the determination of hippuric and orotic acid in whey.

A rapid method was developed for the simultaneous determination of hippuric and orotic acid in rennet whey by capillary zone electrophoresis using an uncoated capillary utilizing a 0.04 M amino-2-methyl-1,3-propanediol (AMPD)-N,N-bis(2-hydroxyethyl) glycine (BICINE) buffer (pH 8.8) with UV detection at 254 and 280 nm. Whey proteins were removed by ultrafiltration. The method was evaluated for external, internal and standard addition procedures for both peak areas and peak heights. The use of an internal standard (sorbic acid) eliminated injection errors and gave, when applied to peak areas, the same levels for hippuric and orotic acid in those obtained with high-performance liquid chromatography. Relative standard deviations were 1-2%. Peak heights gave erratic results owing to sample matrix effects on peak widths.

Dairy Products↗
PubMed1983

Metabolic conversion of orotic acid hydrazide into a nucleotide in mouse and rat liver.

When [2-14C] orotic acid hydrazide (OAH) was injected i.p. in mice the bulk of the radioactivity of the acid-soluble fraction of liver was found in a metabolite obviously not identical with natural pyrimidines known so far as elucidated by chromatographic methods. This compound is also formed in vitro by the cytosolic fraction of mouse liver or by purified orotate phosphoribosyltransferase/orotidine-5'-phosphate decarboxylase (OPRTase/ODCase) provided that PRPP is present in the medium. Using alkaline hydrolysis and snake venom to split off the hydrazine- and the phosphate group, respectively, the metabolic product of OAH was identified as a nucleotide, orotic acid hydrazide nucleoside monophosphate. The identity of OMP and orotidine thus formed was confirmed by thin-layer chromatography.

Animals↗
PubMed1979

Absence of fatty livers in rhesus monkeys fed orotic acid.

Pairs of rhesus monkeys were fed for 10 wk a basal diet containing 1% orotic acid or 10% nonfat milk powders. Amounts of total lipids in the liver and hepatic morphology were normal after 10 wk indicating that orotic acid in the diet did not induce fatty livers in rhesus monkeys.

Animals↗
PubMed1993

Ribonucleotide reductase: a possible target for orotic acid induced mitoinhibition in normal hepatocytes in primary culture.

The present study was designed to determine the mechanism by which orotic acid, a rat liver tumor promoter, inhibits DNA synthesis in normal hepatocytes in primary culture. Our results indicate that orotic acid inhibited the epidermal growth factor induced expression (mRNA) of both M1 and M2 subunits of ribonucleotide reductase while the expression of c-fos, c-myc, c-Ha-ras and beta-actin was not inhibited to any significant extent. These studies suggest that ribonucleotide reductase may be one target for orotic acid-induced mitoinhibition.

Adenosine Triphosphate↗
PubMed1978

[Effect of orotic acid on the regeneration processes after gastrectomy].

Experiments on animals have shown a favourable effect of orotic acid upon reparative regeneration processes in injured abdominal wall and stomach. In the clinic the administration of orotic acid favoured the decrease of the incidence of postoperative complications from 32% to 14% and the acceleration of the wound healing by 30%.

Animals↗