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Alloxan treatment induces a decrease of orotic acid content in various organs of carp, frog, pigeon and rat, parallel to a decrease of liver and muscle glycogen content. Loss of orotic acid and glycogen cannot be prevented by orotic acid and carbamyl phosphate given i.p. Mice, rats and pigeons use up and excrete exogenous orotic acid rapidly, but carps and frogs accumulate it.
Urinary excretion of orotic acid is increased in many inborn errors of ureagenesis and some other diseases. Urine orotic acid is found to be accurately measured by gas chromatography-mass spectrometry (GC-MASS) under the conditions for organic acids analysis. Therefore, GC-MASS analysis of urine is also helpful in the diagnosis of urea cycle disorders in patients with hyperammonemia. Specific tests for orotic acid measurement are not necessary if urine organic acids analysis is available.
The synthesis, blood plasma turnover and urinary excretion of the orotic acid in normo- and hyperargininaemic sheep was investigated. The whole-body orotate formation was evaluated indirectly by the measurement of urinary orotate excretion after blockage of pyrimidine pathway with 6-azauridine (4 hour i.v. infusion of 0.2 mg.kg-1.min-1). Simultaneous infusion of L-arginine (2.5 mumols.kg-1.min-1) significantly elevated the blood plasma arginine, ornithine and urea level, however, it did not significantly influence urinary orotate excretion. In normoargininaemia blood plasma turnover of exogenous orotic acid amounted to 4.9 min and 67% of this compound was eliminated through the kidneys. The renal clearance of orotic acid amounted to 21.7 ml.min-1.kg-0.75. Hyperargininaemia elevated blood plasma turnover to 8.2 min, and diminished the renal clearance of this metabolite to 13.7 ml.min-1.kg-0.75. These results indicate that hyperargininaemia and hyperornithinaemia do not change the whole body synthesis of orotic acid in sheep but they can affect renal excretion of this metabolite, particularly at the rate of tubular secretion close to saturation.
The effects of acute food deprivation and subsequent refeeding on urinary orotic acid excretion were examined in nine healthy adult male subjects. During inpatient metabolic ward conditions, the volunteers were fed a nutritionally complete, pyrimidine- and purine-free diet for three days and subsequently underwent a ten-day fast followed by a ten-day period of refeeding by total parenteral nutrition. Mean daily excretion of 4.33 +/- 0.23 mg (2.77 +/- 0.12 mg/g creatinine) of orotic acid during the enterally fed state was significantly reduced (mean 46 +/- 5%) in all subjects during starvation. This reduction in the excretion of orotic acid during starvation is more likely related to a lowered rate of production and utilization. The starvation adaptation of orotate excretion occurred more rapidly than did the decrease in urinary nitrogen loss. All subjects showed an increase (mean 48 +/- 14%) in the excretion of orotic acid during the first day of refeeding which continued throughout the refeeding phase. A significant positive correlation was shown between the daily orotic acid excretion and nitrogen intake (r = 0.98) or protein balance (r = 0.83). The response to refeeding of acutely malnourished normal male is an increase in orotic acid excretion with a decrease in whole body protein catabolism.
Effects of dietary supplementation of orotic acid to a diet containing the casein protein were compared with diets containing egg protein, soy protein, or wheat gluten on lipid levels in the liver and serum and activities of ornithine carbamoyltransferase (OCT) and alanine aminotransferase in the serum of rats. We found that supplementation of orotic acid to each diet increased the contents of the liver total lipids, triacylglycerol, and phospholipids compared with those not supplemented. The contents of liver total lipids, triacylglycerol, cholesterol, and phospholipids in rats fed the casein diet were significantly higher than those of rats fed the other three diets when orotic acid was supplemented. The levels of triacylglycerol, cholesterol, and phospholipids in the serum of rats fed the casein diet were markedly decreased by addition of orotic acid. The supplementation of orotic acid significantly increased the activities of both serum OCT and alanine aminotransferase in rats fed the casein diet, but not in rats fed the other diets. In conclusion, liver lipid accumulation induced by dietary orotic acid depends on the type of dietary protein. The enhancement of serum OCT activity may result from liver lipid accumulation in rats fed the casein diet supplemented with orotic acid, demonstrating hepatic damage.
90 urine samples obtained in three lamb trials and one experiment using adult wethers were analyzed for their contents of orotic acid and creatinine. The average daily excretion of orotic acid accounted for 0.5 mg to 1.5 mg (35 micrograms to 130 micrograms/W0.75) with a high individual variation. Correlation coefficients between orotic acid and other urinary constituents were low indicating an entirely different response to metabolic variations. There was only a weak relationship to live weight, protein retention and rumen fluid traits. Defaunation reduced the orotic acid excretion (significant in the adult wethers) whereas the addition of rumen-protected lysine as well as the use of different dietary carbohydrate sources were without effect. The urinary excretion of creatinine increased with live weight and age from 0.4 g/d in the 20 kg lambs to 1.7 g/d in the adult 53 kg wethers. The correlations with live weight were close whereas the apparently negative correlation with protein retention was not real as could be evaluated by calculation of the partial correlations. There was a close correlation of creatinine with total N, urea and allantoin. Neither defaunation nor rumen-protected lysine and the kind of carbohydrate source had significant effects on creatinine. The use of orotic acid and creatinine as indicators of metabolic disorders were discussed. Easy application in practical diagnosis without quantitative urine collection might be possible by the determination of orotic acid in the milk of cows and of the creatinine/N ratio in urine.
The concentration of orotic acid in dry whey ranged between 64 and 146 mg/100 g and appeared dependent on whey type. The orotic acid of modified whey products, prepared commercially by electrodialysis, ultrafiltration, gel filtration, or polyphosphate precipitation was between 7 and 124 mg/100 g, which was less than that of dry whey. It appears that whey processing methods do not concentrate orotic acid in whey fractions.
Rapid, sensitive and accurate stable isotope dilution assays were developed for the measurement of orotic acid and uracil in amniotic fluid. The method utilizes [15N2]orotic acid and [15N2]uracil as internal standards, isolation by liquid partition chromatography and quantitation by chemical ionization selected ion monitoring gas chromatography-mass spectrometry. Orotic acid at a concentration of 0.26 +/- 0.05 mumol/l and uracil at a concentration of 0.55 +/- 0.13 mumol/l were detectable in normal amniotic fluid. As affected fetuses with argininosuccinate synthetase or ornithine carbamoyl transferase deficiency showed no significant elevation of orotic acid and/or uracil in their surrounding amniotic fluids, this method unfortunately seemed not to be useful for prenatal diagnosis of these inherited disorders. Nevertheless, it provides significant advantage over available methods for the quantitation of orotic acid and uracil in which the analysis of these compounds must be very accurate, highly specific and sensitive (e.g. detection of heterozygosity for ornithine carbamoyl transferase deficiency).
The release of (14)CO(2) from [7-(14)C]orotic acid was measured in isolated perfused normal and regenerating rat livers. With some limitations, the release of (14)CO(2) from [7-(14)C]orotic acid can be used to estimate UMP synthesis in perfused livers. Isolated perfused livers rapidly pick up labelled orotic acid added to perfusate and convert most of it into UMP. Perfused regenerating livers produce approx. 2.5 times as much UMP/g of liver as do perfused normal livers. However, the absolute amount of orotic acid converted into UMP is higher in perfused normal livers than in perfused regenerating livers. Perfused regenerating livers do not differ in their orotic acid uptake and UMP synthesis from livers of comparable size in which regeneration is not taking place. The total amount of orotic acid taken up by the liver (rather than the rate of uptake) and the size of the liver appear to be the determining factors in UMP production. The results suggest that the decrease in liver size caused by partial hepatectomy may be in itself sufficient to account for an increase in the flow of metabolites in the pyrimidine pathway at the early stages of liver regeneration.
Male Fischer 344 rats initiated with 1,2-dimethylhydrazine 2HCl (100 mg/kg) given 18 hr after partial hepatectomy and exposed to a diet containing 1% orotic acid for 13 months developed a 100% incidence of hepatocellular carcinoma. The creation of nucleotide pool imbalances by dietary orotic acid, for e.g., an increase in uridine nucleotides and a decrease in adenine nucleotides, was considered as a possible mechanism for the promotional effect of orotic acid on liver carcinogenesis. The significance of this hypothesis is that altered nucleotide pools affect both genomic as well as membrane organization. Consistent with this hypothesis is our finding that feeding rats with a diet containing 1% orotic acid for 10 weeks resulted in a liver DNA damage as monitored by its slower sedimentation in alkaline sucrose gradients compared to the corresponding controls. To assess the general applicability of this hypothesis, nucleotide pool imbalances were created by using methods other than feeding orotic acid and their effect on the incidence of gamma-glutamyltransferase positive foci in carcinogen initiated rats was determined. The results obtained indicated that rats initiated with 1,2-dimethylhydrazine.2HCl (100 mg/kg) given 18 hr after partial hepatectomy and exposed to diet deficient in arginine, a regimen that causes an increased synthesis and excretion of orotic acid, or were fed diets containing 1% thymidine or 1% thymine developed greater number of gamma-glutamyltransferase positive foci compared to the corresponding controls fed the basal diets. These results were interpreted to indicate that orotic acid exerts its promotional effect probably by creating an imbalance in nucleotide pools. One of the mechanisms by which an imbalance of nucleotide pools influences the pathogenesis of the carcinogenic process may be by inducing perturbations in the DNA.
The present study was carried out to investigate the effect of orotic acid on ischaemic/reperfused myocardial function and cardiac glycogen content in isolated working rat hearts. In a preliminary series of studies, hearts isolated from male Wistar rats (300-350 g) were perfused with oxygenated Krebs-Henseleit buffer containing cumulative concentrations of orotic acid from 0.01 to 10.00 mg l-1. In the concentration range of 0.01-0.10 mg l-1, orotic acid significantly improved left ventricular function. Therefore, in the second series of studies, rats were treated intravenously with 0.01 mg kg-1 orotic acid for 4 days. Hearts were then isolated and subjected to 30 min of global no-flow ischaemia followed by 10 min of reperfusion. Orotic acid treatment significantly improved post-ischaemic myocardial function and increased pre-ischaemic and post-ischaemic glycogen content of the heart. We conclude that orotic acid improves ischaemic/reperfused cardiac performance and this effect may be based on the elevation of myocardial glycogen content.
Experiments were conducted in sheep to investigate the protective effect of orotic acid versus acetic acid (0.2 g/kg body weight) against the effects of the administration of urea (0.5 g/kg) into the rumen. Blood ammonia levels, motility of the reticulo rumen and food intake were measured. The quantity of ammonia nitrogen produced in the rumen was only 162 +/- 21 mg NH3-N/100 ml 2 hours after the urea and orotic acid addition instead of 229 +/- 31 mg NH3-N for urea and acetic acid. The blood ammonia level was reduced by 47% when orotic acid was used instead of acetic acid. The long-lasting inhibition of the contractions of the reticulo-rumen by urea was restricted to 120 and 80 min by acetic and orotic acid respectively. The amount of food intake which was halved by urea was only reduced by 40.7% when both acetic acid and urea were administered. Reduction in the amount of food intake due to urea was suppressed by the administration of orotic acid.
We report the effect of the ornithine transcarbamylase (OTC) transgene composed of 1.3 kb of the 5' flanking region of the rat OTC gene fused to rat OTC cDNA on urinary orotic acid excretion in OTC-deficient spf-ash (sparse-fur with abnormal skin and hair) mice during overnight-starvation and nitrogen loading. During starvation, spf-ash mice with about 6% and 2% of control levels of OTC activity in the liver and small intestine excreted a large amount of orotic acid in the urine. Transgenic spf-ash mice with about 10% and 30% of the control OTC activities in the liver and small intestine did not excrete more than the normal level of orotic acid. Accidental parasitization of transgenic spf-ash mice with ticks (Myocoptes musculinus) resulted in decrease of the OTC activities in the liver and small intestine to the levels in spf-ash mice, and increased excretion of orotic acid. During extermination of the ticks, the mice showed varied levels of OTC activity and orotic acid excretion. On nitrogen loading, transgenic spf-ash mice as well as spf-ash mice excreted larger amounts of orotic acid, while control mice showed no increase in its excretion. The levels of urinary orotic acid were inversely correlated to the logarithms of the OTC activities in the liver and small intestine, the correlation being significantly higher with intestinal OTC than with hepatic OTC activity. These results suggest that the level of OTC activity in the small intestine is important for production of orotic acid.
Orotic acid (OA) is an intermediate in the pyrimidine pathway. The main source of OA in the human and animal diet is bovine milk and its products. OA significantly inhibited the stimulation of protein synthesis by FCS derived growth factors in L6 myoblasts. An increasing OA concentration (0.001 mM, 0.01 mM, and 0.1 mM) in a medium containing 2% FCS decreased the proliferation of L6 myoblasts (as measured by the number of cells) as well as the incorporation of traced thymidine into cellular DNA after 24 h incubation. This mitoinhibitory effect was accompanied by a significant reduction of ornithine decarboxylase (ODC) activity, an enzyme which is believed to be a valuable index of cell proliferation. A drop in the cytosol spermine level of L6 myoblasts treated with OA also occurred. A simultaneous, significant, compensative increase of S-adenosylmethionine decarboxylase (SAMDC) activity was noted. The addition of putrescine (2 microM), a product of ODC activity, abolished the depressional influence of OA on protein synthesis in L6 myoblasts, thus confirming its interference with the polyamine pathway. Dibutyryl-cAMP (0.05-0.2 mM) or adenine (25 microM) supplementation, regardless of OA concentration, significantly attenuated the mitoinhibitory effect and its inhibitory action on protein synthesis. This may suggest the existence of a purine deficiency in OA-treated myoblasts. These experiments indicate that increasing cellular OA concentration inhibits cell growth probably by disturbances in the chain of early events (synthesis of cyclic purine mononucleotides, and activity of the ODC/polyamine system), normally evoked by growth stimulating factors.
The effect of orotic acid on the development of compensatory pulmonary hypertrophy has been studied in the clinic and in the experiments (71 patients, and 349 rats) carried out with the use of morphologic, biochemical cytochemical, immunologic and clinical methods, and also through autoradiography. The results of the study prove the effect of the drug upon the pulmonary regeneration. Experimental findings have shown that behind the stimulating effect of the drug there is the activation of the synthesis of nucleinic acids, the rise of the mitotic activity of the interalveolar membranes cells of the lung remnants. An essential increase of the lymphocytic dehydrogenase activity of the peripheral blood occurred in response to the effect of the drug.
In rats treated with phenobarbital for 3 days and simultaneously fed a semisynthetic diet containing 1.0% orotic acid, the extent of the increases in liver microsomal phosphatidylcholine, phosphatidylethanolamine, total RNA, total protein, and cytochrome P-450 were significantly greater than they were in rats treated identically with phenobarbital but without dietary orotic acid. This is attributed primarily to the stimulation of hepatic phosphatidylcholine synthesis by dietary orotic acid. In the absence of phenobarbital, orotic acid was shown to cause some increase in liver smooth endoplasmic reticulum components, but not cytochrome P-450. Orotic acid also decreased the activity of microsomal phosphatidylethanolamine N-methyltransferase, which may have contributed to the increase in the microsomal content of phosphatidylethanolamine. The hypothesis is advanced that phospholipid availability is a limiting factor in the hepatic response to phenobarbital. When more phospholipid is available to provide the structural framework for biogenesis of endoplasmic reticulum, all of the hepatic actions of phenobarbital, including induction of cytochrome P-450, are amplified.
BACKGROUND: We have previously shown that infarction impairs recovery of global function after subsequent cardioplegic arrest and that therapy with orotic acid improves recovery. The aim of this study was to measure the effect of infarction on regional and global left ventricular function and to determine whether orotic acid exerts a beneficial effect exclusive of the effects of cardioplegia. METHODS: Acute myocardial infarction was produced in dogs. They then received either orotic acid or placebo (control) orally (n = 12 per group). Fractional radial shortening and systolic wall thickening were measured by two-dimensional echocardiography before and 1 and 3 days after infarction with and without beta-adrenergic blockade, and in 6 dogs up to 9 days after infarction. Global function was measured under anesthesia 4 days after infarction. RESULTS: In control animals, fractional radial shortening in the infarct decreased from 20.6% +/- 5.1% before infarction to 3.0% +/- 2.2% at day 1 and to 1.9% at day 3 (p < 0.01). In the border zone radial shortening declined from 21.9% +/- 3.7% to 11.0% +/- 2.3% at day 1 and 9.3% +/- 2.8% at day 3 (p < 0.05). In the noninfarcted myocardium radial shortening also declined from 27.1% +/- 1.9% before infarction to 18.3% +/- 2.3% on day 1 (p < 0.05) and to 16.0% +/- 2.8% on day 3 after infarction (p < 0.05) with recovery to preinfarct levels by 9 days after infarction. These findings were confirmed by measurements of systolic thickening. Before infarction beta-receptor blockade decreased fractional shortening in all regions of the left ventricle, but this effect was absent on day 3 after infarction, implying that the myocardium had become less responsive to beta-adrenergic stimulation. Measurements of global function 4 days after infarction showed marked depression of stroke work. There was no effect of orotic acid treatment on regional or global function. CONCLUSIONS: Myocardial infarction causes reversible depression of resting function and beta-adrenergic responsiveness in the remote and border zone areas, which is not prevented by metabolic therapy with orotic acid. This finding may explain the adverse response of the infarcted heart to cardioplegic arrest.
AIM: In this study; orotic acid levels in the milk of smoking and non-smoking mothers were investigated by high-performance liquid chromatography (HPLC). RESULTS: It was found that the amount of orotic acid in the milk of smoking mothers (3.92+/-0.20 micro g/ml) was higher than that of non-smoking mothers (1.66+/-0.15 micro g/ml). Orotic acids levels in the milk of smoking mothers in comparison with non-smokers were found to be statistically significant (P<0.005). CONCLUSION: Smoking may have increased the orotic acid levels by affecting pyrimidine biosynthesis pathway.