A possible relationship of vitamin B13 to orotic acid.
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Folic Acid↗
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DEOXYRIBONUCLEIC ACID SYNTHESIS BY CULTURED MAMMALIAN CELLS IN THE PRESENCE OF OROTIC ACID.
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Animals↗
Pulsed electrochemical detection of orotic acid by an activated potential waveform at a gold working electrode following anion-exchange chromatography.
The application of activated pulsed amperometric detection (APAD) for the determination of orotic acid (OrA) in real samples at a gold working electrode in alkaline solutions, in combination with anion-exchange chromatography, is reported. Such an activated potential waveform was designed with an initial step that involves the formation of redox active species (e.g., adsorbed AuOH/AuO), which in turn is halted upon lowering the applied potential at the detection value while the adsorbed gold hydroxide/oxide species are still catalytically active. A direct comparison between the activated potential waveform and the more commonly used pulsed amperometric detection showed roughly a 20-fold increase in sensitivity. The chromatographic separation of OrA was accomplished by using a microbore anion-exchange column eluted with an isocratic mobile phase composed of 100 mM NaOH+40 mM NaNO(3). Orotic acid was determined at the concentration ranges of 0.2-30 microM (r=0.9997) with an absolute detection limit of 80 pg (10 microL injected). The levels of OrA in cows' milk samples evaluated by standard additions, using 5-aminoorotic acid as an internal standard, ranged from 56 to 126 mg/L. Lower levels were found in raw sheep's milk (<20 mg/L). The assay is shown to be very useful in clinical investigations where relatively high levels of OrA in human urine are correlated to metabolic diseases.
Animals↗
Decreased utilization of [2-14C]orotic acid for the synthesis of cytidine nucleotides in rat liver after administration of alpha-hexachlorocyclohexane.
Administration of alpha-1,2,3,4,5,6-hexachlorocyclohexane (alpha-HCH) to rats decreased the utilization of [2-14C]orotic acid for the synthesis of liver cytidine nucleotides. The specific radioactivities of uridine components of the acid-soluble pool and rRNA increased during the first hours of treatment with the drug. Later on the specific radioactivities of uridine nucleotides remained unchanged, while those of cytidine components decreased gradually. Administration of hydrocortisone increased the incorporation of labelled orotic acid into rRNA cytidylic acid.
Animals↗
Incorporation of orotic acid into nucleotides and RNA in mouse organs during 60 minutes.
Mouse kidney and liver were found to increase their levels of radioactivity above that of serum from 2 to 60 min after administration of [6-14C]orotic acid. In spleen, thymus and brain, the radioactivity level reached a maximum soon after the injection and then decreased, as did that in serum. Sixty minutes after the injection, 44% of the administered isotope dose was found in the kidneys, 22% in the liver and 0.75% in the spleen. The 14C activity in liver UTP increased rapidly and then remained constant for 60 min. The ratio between the activities in uridine phosphates and UDP-sugars was 3:4 from 10- 60 min after injection. In the liver and kidneys, the RNA 14C activities at 60 min after injection were 15% of the activity in their acid-soluble fractions. Intraperitoneal administration was found to be preferable to intravenous administration for studies on nucleotides and RNA in mouse liver, due to the delayed incorporation of the [14C]orotic acid activity into the nucleotide pool.
Animals↗
Studies of pyrimidine nucleotides with orotic acid 2-C14 and P32.
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Nucleic Acids↗
Failure of orotic acid to suppress activity of plasma lecithin:cholesterol acyltransferase.
There are theoretical reasons for postulating a relationship between turnover of triglyceride-rich lipoproteins and plasma cholesterol esterifying activity, and some experimental evidence exists to support such a hypothesis. Orotic acid has been given to rats to determine whether blocking the hepatic release of very-low-density lipoproteins would also reduce hepatic secretion of lecithin:cholesterol acyltransferase (LCAT). No evidence of such an effect was found. In a single human experiment orotic acid exerted only minimal effects on serum concentrations of lipoproteins, and LCAT activity was apparently unaffected.
Adult↗
Nitrogen retention, muscle creatine and orotic acid excretion in traumatized rats fed arginine and glycine enriched diets.
Male, Sprague-Dawley rats were subjected to the trauma of laparotomy under sodium pentothal anesthesia. Apparent N retention (N intake - Urinary N) was studied when these rats were fed a 25% casein diet either unsupplemented or enriched with arginine plus glycine or with ornithine plus glycine. These amino acids occur in particularly high concentrations in skin and connective tissue and might, therefore, be required in greater amounts for tissue repair. In one experiment muscle creatine content and orotic acid excretion in the urine were determined. We found that laparotomy carried out under sodium pentothal anesthesia was a highly reproducible form of trauma which resulted in a significant decrease in apparent N retention. Supplementing a 25% casein based diet with arginine and glycine significantly improved apparent N retention both in untraumatized as well as in traumatized rats. Ornithine was less effective than arginine in improving apparent N retention. Urinary orotic acid excretion was significantly increased in rats fed the unsupplemented casein diet, regardless of the imposition of trauma. Muscle creatine content was significantly increased by the supplementation of the diet with arginine plus glycine. The beneficial effect of arginine-plus-glycine enrichment in traumatized rats does not appear to be due to an arginine deficit needed for the detoxification of ammonia from excess amino acids but may be related to creatine synthesis and turnover.
Amino Acids↗
Increasing the interval between initiation and the onset of exposure to orotic acid decreases its promoting effect on rat liver carcinogenesis.
The present study was designed to determine whether a delay in the start of the promoting regimen after the administration of a carcinogen would influence the promoting efficacy of orotic acid on the development of hepatocellular carcinoma in rats. Male Fischer 344 rats weighing 130-150 g were injected with a single dose of diethylnitrosamine (200 mg/kg body wt i.p.) then divided into 3 groups: groups 1 and 2 were given semi-synthetic basal diet or the same diet containing 1% orotic acid (OA) respectively starting 1 week after the carcinogen; group 3 received the OA diet starting 5 weeks after the administration of diethylnitrosamine. Animals from these 3 groups were sacrificed after 25, 32, 42 and 60 weeks of being fed their respective diets. The results indicated that delaying the start of the OA diet after the carcinogen resulted in about a 50% decrease in the incidence of hepatic nodules and/or hepatocellular carcinomas at various time points during the experiment. This decrease in promoting efficacy of OA was not apparently explainable by lack of metabolic effects of OA, at least in terms of induction of nucleotide pool imbalance, a condition that appears to be important for OA to exert its tumor promoting effects.
Animals↗
Automated determination of orotic acid, uracil and pseudouridine in urine by high-performance liquid chromatography with column switching.
A column-switching high-performance liquid chromatographic method, requiring no sample preparation apart from filtration, is described for quantification of urinary orotic acid, uracil and pseudouridine. The analyses were carried out using a reversed-phase octadecylsilane-bonded column for sample clean-up and a cation-exchange column for separation; 5-20 microliters samples of urine were directly analysed, and more than 100 samples could be analysed consecutively. Each sample required only 30 min. Detection limits of these compounds were 5 pmol. Creatinine-related urinary uracil excretion was lowest in the newborn period (17.3 +/- 14.4 mumol/g of creatinine). A patient with partial ornithine transcarbamylase deficiency and his mother usually excreted a high level of uracil during the period of normal orotic acid excretion and normal serum ammonia level.
Adolescent↗
[Incorporation of [2-14C orotic] acid into chromatin RNA of tissues of animals of various ages].
The structure and biological activity (the level of the labelled precursor incorporation into RNA) of active and repressed chromatin of the liver and small intestine mucosa were studied in adult (6-8 months) and old (24-26 months) rats. The content of repressed chromatin fraction in both tissues is found to increase with age. In the liver of old rats the level of [14C[ orotic acid incorporation into RNA of chromatin fractions decreases, radioactivity of the acid-soluble fraction being unchanged. In the small intestine mucosa a high leve of [14C] orotic acid incorporation into chromatin RNA with ageing is due to an increase in permeability of the mucosa cells.
Aging↗
Influence of orotic acid and estrogen on hepatic lipid storage and secretion in the goose susceptible to liver steatosis.
Fatty liver in the goose results from an increased hepatic lipogenesis in response to overfeeding, together with a deficient secretion of triacylglycerol as very-low-density lipoproteins (VLDL). Orotic acid and estrogen, which both modify lipid metabolism in the liver, were used in male geese as tools to understand the alterations of liver lipids and plasma lipoproteins during the induction of liver steatosis. Liver lipids were analyzed after solvent extraction and plasma lipoproteins after separation by density gradient ultracentrifugation. Contrary to what is known in the rat, orotic acid (1% in food for 2 weeks) failed to induce liver steatosis. In force-fed geese, liver weight increased from approximately 100 g to approximately 800 g in 2 weeks, as a consequence of a specific accumulation of triacylglycerol. In both groups, VLDL contained less triacylglycerol (35%) than normal. Such an uncoupling of triacylglycerol synthesis and secretion, of which the precise reason is still unknown, may facilitate their accumulation when force-feeding increases hepatic lipogenesis. As with force-feeding, triacylglycerol synthesis was enhanced by estrogen, but their secretion as VLDL was very efficient and prevented liver steatosis almost completely. Since HDL concentrations were considerably decreased by estrogen, VLDL were the main lipoprotein species, with 48 g/l and 62% triacylglycerol. Where estrogen-treated geese were force-fed concomitantly, VLDL concentration was even higher (62 g/l), but triacylglycerol secretion could not prevent liver steatosis (liver weight 640 g). The data are discussed in relation to in vitro studies showing that channelling of triacylglycerol towards secretion as VLDL or hepatic storage depends on their residence time in the different intracellular compartments.
Animal Feed↗
The regulation of ribonucleoside diphosphate reductase by the tumor promoter orotic acid in normal rat liver in vivo.
Our earlier studies have shown that in normal hepatocytes, orotic acid (OA) inhibits DNA synthesis induced by several growth factors in vitro and after two-thirds partial hepatectomy (PH) in vivo. As in the normal liver OA induces an imbalance in nucleotide pools (specifically, an increase in uridine nucleotides, including deoxyuridine nucleotides, and a decrease in adenosine nucleotides, including ATP) and creation of this imbalance is crucial for the mitoinhibitory effects of OA, we hypothesized that ribonucleoside diphosphate reductase (RNR), a key enzyme in DNA synthesis that is regulated by nucleotide/deoxynucleotide levels, might be one of the targets for the inhibition of DNA synthesis by OA. To test this hypothesis, we subjected male Fischer 344 rats (130-150 g) to two-thirds PH in the absence or in the presence of OA (a 300-mg tablet of OA methyl ester implanted intraperitoneally at the time of two-thirds PH). The rats were killed at different times later, and their livers were processed for analysis of levels of RNR enzyme activity, protein, and mRNA transcripts. The results obtained indicated that treatment with OA resulted in a near-100% inhibition of RNR induced by two-thirds PH in rat liver, as monitored by enzyme activity and protein level. Furthermore, this inhibition was paralleled by a decrease in the mRNA transcripts for both the M1 and M2 subunits of RNR. Nuclear run-off assays indicated that this decrease in the levels of mRNA transcripts could not be attributed to an effect on transcription. However, administration of OA 20 h after two-thirds PH, when RNR mRNA transcripts were maximally induced, resulted in increased degradation of the RNR M1 and M2 subunits. Taken together, these results indicate that OA treatment decreases RNR levels induced by two-thirds PH, at the levels of enzyme activity, protein, and mRNA transcripts, and the decreased levels of mRNA transcripts appeared to be due to increased degradation of the transcripts.
Animals↗
Effects of skim milk, skim milk yogurt, orotic acid, and uric acid on lipid metabolism in rats.
The effects of feeding two milk products (skim milk and skim milk yogurt) and two proposed hypocholesterolemic factors (orotic acid and uric acid) on serum cholesterol (HDL, LDL, total, HDL/Total and HDL/LDL), liver lipids (total liver lipids and liver cholesterol), and aortal cholesterol were studied. Ten groups, of nine rats each, were fed isocaloric Chow-based diets containing water, 45% skim milk (SM), 45% skim milk yogurt (SMY), and 0.0025% orotic acid (OA) or 0.001% uric acid (UA), without or with cholesterol. The SM diet (with cholesterol) resulted not only in lower total cholesterol (P < 0.10), LDL cholesterol (P < 0.05), aortal cholesterol (P < 0.01), and liver cholesterol (P < 0.10), but also in increased HDL (P < 0.05) and HDL/LDL (P < 0.10) cholesterol ratio. The SMY diet, on the other hand, resulted in lowered total serum cholesterol (P < 0.05) and aortal cholesterol (P < 0.01) and in higher LDL (P < 0.05) cholesterol. The hypocholesterolemic effects were more marked for SM than for SMY. Addition of OA and UA to diets increased serum cholesterol, LDL cholesterol, and total liver lipids; the OA diet also increased liver cholesterol. Neither OA nor UA alone was the factor responsible for the hypocholesterolemic effects seen with SM and SMY feeding.
Journal Article↗
Early changes of liver phospholipase C activity in rats fed an orotic acid supplemented diet.
In this study of the effect of an orotic-acid (O.A.) diet on the activity of membrane-bound phosphoinositide-specific phospholipase C (PL-C) of rat liver, its enzymatic activity was evaluated in vitro on membranes obtained from the hepatic tissue of male Wistar rats fed a diet containing 1% O.A. for 2 and 5 days and from control rats. The rate of breakdown of labelled phosphatidylinositol-4,5-bisphosphate (Ptdins-P2) added to the isolated membranes was measured both in the absence and in the presence of guanosine-5'-O-thiotriphosphate (GTP gamma S). The enzyme stimulation by bombesin was also analysed. PL-C activity proved to be deeply and early modified by O.A. The basal activity was increased 2 days after feeding on the O.A.-supplemented diet, but the difference from control rats was no more significant after 5 days of this diet. The most interesting changes concerned the response to bombesin; the hormone failed to induce any stimulation of PL-C in O.A.-treated rats after either 2 or 5 days of diet, whereas it nearly doubled Ptdins-P2 breakdown in the liver membranes from control rats. The lack of any stimulation of the phospholipase C by bombesin in O.A.-treated rats indicates a deep impairment of this signal transmission system; its possible causes and consequences are discussed.
Animals↗
RNA labelling with 3H-orotic acid and 3H-fluorouracil of rat liver tumour following transient hepatic arterial ischaemia.
Recent studies have demonstrated that transient (1 h) hepatic arterial ischaemia is followed by increased incorporation of labelled thymidine into tumour DNA 24 h later. The present study aimed at investigating if and when there is a corresponding increase in incorporation of labelled 5-fluorouracil (5-FU) or orotic acid into tumour tissue. Incorporation was studied at 0, 6, 24 and 48 h after discontinuation of transient hepatic arterial ischaemia in Wistar-Furth rats having liver tumour. The transient ischaemia was followed by increased RNA and RNA/DNA ratios in normal liver but not in tumour. Incorporation of orotic acid into RNA and DNA was unchanged in tumour but increased at 0 and 6 h in normal liver. Incorporation of 5-FU decreased with time in liver and tumour DNA and in tumour RNA. It is suggested that 5-FU has an optimal effect on tumour tissue when infused immediately after transient hepatic arterial ischaemia.
Animals↗
Effect of 1,3-dithia-2-thioxo-cyclopent-4-ene and its derivatives on liver injury induced by carbon tetrachloride and orotic acid in rats.
The protective effect of 1,3-dithia-2-thioxo-cyclopent-4-ene (DT827A) and its two derivatives of 4-phenyl-1,3-dithia-2-thioxo-cyclopent-4-ene (DT827B) and 4-(4-fluorophenyl)-1,3-dithia-2-thioxo-cyclopent-4-ene (DT827C) on liver injury induced by carbon tetrachloride (CCl4) and orotic acid was studied using male rats. The approximate lethal doses were about 100 mg/kg for DT827A-treated animals and more than 800 mg/kg for the other two compounds-treated groups. Single oral administration of the three test compounds at the dose levels of 2 and 10 mg/kg 1 hour before CCl4 exposure revealed a protective effect on the findings of centrolobular necrosis, balloon cells and macrophage infiltration in histopathological findings in livers in the order of DT827B-treated rats > DT827A-treated rats > DT827C-treated rats. Repeated oral administration of the compounds at the dose levels of 2 and 10 mg/kg/day for 10 consecutive days revealed a protective effect against liver injury on the findings of centrolobular necrosis, balloon cells and macrophage infiltration in the order of DT827B-treated rats > DT827A-treated rats [symbol: see text] DT827C-treated rats. Simultaneous administration of the compounds at the dose level of 10 mg/kg/day together with a high sucrose diet containing orotic acid for 12 days revealed an inhibitory effect on fatty liver formation in the order of DT827B-treated rats > DT827C-treated rats > DT827A-treated rats. A hepatoprotective potential of the DT827 series compounds was suggested under the conditions of these studies, and DT827B was considered to be the most effective.
Administration, Oral↗
Influence of ethanol, nicotinamide, orotic acid and caffeine upon the induction of tyrosine aminotransferase, the NAD content and the ADPR transferase activity in rat liver.
Chronic uptake of ethanol leads to irreversible damage of liver cells. Until now the cause of this alteration is unknown. To get more information experiments presented in this paper were performed. Contrary to normal fed animals the enzyme tyrosine aminotransferase (TAT) can be induced by ethanol in starved rats. Orotic acid induces the TAT at a dose of 500 mg/kg. This effect is enhanced to some extent by ethanol. Ethanol increases the minor effect of 50 mg/kg caffeine on TAT induction markedly. Only 500 mg/kg nicotinamide (NA) enhances TAT activity. Here ethanol has a minor stimulatory effect. A combination of nicotinamide with orotic acid or with caffeine leads to substances with a higher effect on TAT induction. Besides nicotinamide and its derivatives only caffeine changes the NAD+ + NADH content of the liver. Ethanol and caffeine reduce the activity of the ADPR transferase. The results indicate that the effect of ethanol might be due to interference with NAD-adenoribosylation metabolism.
Adrenalectomy↗