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PubMed2003

Rapid determination of orotic acid in urine by a fast liquid chromatography/tandem mass spectrometric method.

Quantification of orotic acid (uracil-6-carboxylic acid) in urine is an important tool to diagnose some inherited diseases, such as urea cycle disorder (OTCD) and hereditary orotic aciduria. New rapid analytical methods are necessary to provide high-throughput orotic acid analyses. A new analytical method has been developed for the rapid analysis of orotic acid in urine by liquid chromatography coupled with ion spray tandem mass spectrometry (LC/MS/MS). After a sample dilution 1:20, the analysis was performed in the selected reaction monitoring mode in which orotic acid was detected through the transition m/z 155 to 111. The retention time was 3.9 min in a 4.5-min analysis. Daily calibration between 0.5-5.0 micromol/L of orotic acid, corresponding to 10-100 micromol/L in urine before the 1:20 dilution, offered consistent linearity and reproducibility. Interassay coefficient of variance (c.v.) was 4.97% at a mean concentration of 10.99 micromol/L. The sensitivity and specificity of tandem mass spectrometry permitted a high volume of analyses of orotic acid. The sample preparation is simple, inexpensive and not time demanding.

Calibration↗
PubMed1994

Sequential histopathological analysis of hepatocarcinogenesis in rats during promotion with orotic acid.

In the present study, sequential histopathological changes during hepatocarcinogenesis promoted by orotic acid were examined. Male Fischer 344 rats were given 1,2-dimethylhydrazine.2HCl (100 mg/kg, i.p.) 18 h after 2/3 partial hepatectomy. After 1 week of recovery, they were divided into 2 groups; group 1 was continued on a semisynthetic basal diet while the group 2 received the basal diet containing 1% orotic acid. Rats were sacrificed after 5, 10, 20, 29, 40 and 53 weeks of promotion. Histopathological analysis indicated that emergence of hepatocellular carcinomas was preceded first by foci of morphologically and histochemically altered hepatocytes and then by the appearance of hepatocyte nodules. Clear cell foci, eosinophilic ground glass foci and gamma-glutamyltransferase positive foci were detectable after 5 weeks in initiated rats fed orotic acid. Hepatocyte nodules developed in 56% of the rats after 20 weeks of promotion, while the first hepatocellular carcinoma was observed in one rat sacrificed after 29 weeks of orotic acid promotion. Cancer incidence steadily increased with the duration of the orotic acid treatment and 59% developed hepatocellular carcinomas with 30% metastasis to lungs by 53 weeks of promotion. A relevant feature of this model is that during exposure to orotic acid no liver hyperplasia, nor bile duct or oval cell proliferation were seen and the liver architecture in the tissue surrounding focal lesions was well preserved throughout the sequence.

1,2-Dimethylhydrazine↗
PubMed1989

Increased catabolism of phosphatidylcholine to betaine regulates the liver phosphatidylcholine content in rats fed orotic acid.

Feeding a semi-synthetic diet containing 1% orotic acid to rats for one day stimulates the CDPcholine pathway of liver phosphatidylcholine synthesis 4.5-fold without significantly increasing the liver phosphatidylcholine level. The liver betaine level increases 1.6-fold. The present experiments were performed to investigate the source of the increased liver betaine. Orotic acid feeding did not alter the rate of oxidation of 1,2[14C] choline to betaine. After liver phosphatidylcholine was labelled in vivo with 2[14-C]-ethanolamine, over 90% of the choline-derived radioactivity was recovered in liver betaine and this was consistently increased in rats fed orotic acid. It is concluded that the increased synthesis of liver phosphatidylcholine caused by dietary orotic acid is accompanied by an increased rate of liver phosphatidylcholine catabolism, with betaine as the major end-product of the choline moiety.

Animals↗
PubMed1985

Early effects of dietary orotic acid upon liver lipid synthesis and bile cholesterol secretion in rats.

Dietary orotic acid is known to cause impaired fatty acid synthesis and increased cholesterol synthesis in rats. We found that the impaired fatty acid synthesis occurs during the first day of orotic acid feeding and, in studies with albumin-bound [1-14C]palmitic acid, an associated decrease in the rate of esterification of this fatty acid into triacylglycerol, phospholipid, and cholesteryl ester was observed. These changes may result from the known decreases in liver levels of adenine nucleotides or, as reported here, from decreased liver CoASH levels in orotic acid-fed rats. The increase in hepatic cholesterol synthesis occurred during the second day of orotic acid feeding. It was detected by increased incorporation of [1,2-14C]acetate into cholesterol by liver slices and by a 7-fold increase in HMG-CoA reductase activity. At the same time the biliary output of cholesterol was increased 2-fold and studies using 3H2O revealed that the output of newly synthesized cholesterol in bile was increased 5-fold. The content of cholesteryl ester in hepatic microsomes decreased during orotic acid feeding but free cholesterol was unchanged. The findings are interpreted to suggest that the increased bile cholesterol secretion caused by orotic acid is a result of impaired hepatic cholesterol esterification and that the increase in HMG-CoA reductase activity is a result of diminished negative feedback due to the depleted content of cholesteryl ester in the hepatic microsomes.

Acetates↗
PubMed2002

Diagnostic value of urinary orotic acid levels: applicable separation methods.

Urinary orotic acid determination is a useful tool for screening hereditary orotic aciduria and for differentiating the hyperammonemia disorders which cannot be readily diagnosed by amino acid chromatography, thus reducing the need for enzyme determination in tissue biopsies. This review provides an overview of metabolic aberrations that may be related to increased orotic acid levels in urine, and summarises published methods for separation, identification and quantitative determination of orotic acid in urine samples. Applications of high-performance liquid chromatography, gas chromatography, and capillary electrophoresis to the analysis of urinary specimens are described. The advantages and limitations of these separation and identification methodologies as well as other less frequently employed techniques are assessed and discussed.

Chromatography↗
PubMed1999

Plasma concentrations and renal clearance of orotic acid in argininosuccinic acid synthetase deficiency.

Argininosuccinic acid synthetase deficiency (ASD) is a rare disorder of urea cycle metabolism, with pronounced citrullinemia and orotic aciduria being characteristic biochemical features. To further investigate the role of plasma orotic acid and its possible use for monitoring the metabolic status in ASD, we determined plasma orotic acid, amino acid, and ammonium levels in plasma samples collected over a period of 3 years from a patient who is now 8 years of age. Orotic acid plasma concentrations varied widely from less than 1 micromol/l to more than 60 micromol/l. The renal clearance of orotic acid was eightfold the glomerular filtration rate, thus supporting an active mechanism underlying the excretion of this pyrimidine. Data obtained during a metabolic crisis yielded a statistically significant linear correlation of orotic acid plasma levels with those of glutamine and ammonium, which are generally accepted for assessment of the successful treatment of this disorder. Our data revealed no advantage of plasma orotic acid concentrations over the established amino acids (glutamine and arginine) and ammonium for determining acute treatment responses. Since several effects of high levels of orotic acid have been described in mammals, further research is necessary to assess a possible contribution of orotic acid to the pathogenesis of ASD and the use of plasma orotic acid levels in the long-term monitoring of these patients.

Amino Acids↗
PubMed1986

Orotic acid, arginine, and hepatotoxicity.

This communication presents evidence from the literature and recent experiments that describe circumstances wherein arginine may be a conditional dietary essential. Previous work has established that the synthesis of orotic acid (OA), the first pyrimidine formed in the de novo pathway of nucleic acid synthesis, becomes elevated whenever the ammonia load exceeds the capacity of the urea cycle. Under these circumstances, the common intermediate, carbamyl phosphate, leaks from the mitochondria and induces OA synthesis in the cytoplasm. This leads to increased OA excretion in the urine as pyrimidine synthesis escapes feedback control. A deficiency of urea cycle substrates such as arginine, and administration of certain drugs, ammonium salts, urease, or excess amino acids raises orotic acid excretion. Our recent experiments in rats show that OA excretion is also elevated after partial hepatectomy following galactosamine administration, exposure to carbon tetrachloride, or feeding 36% of calories as ethanol. The elevation in OA excretion was suppressed by dietary supplementation with arginine, implying that arginine is conditionally essential. Adult human male alcoholics showed elevated urinary orotic acid-to-creatinine ratios early after drinking episodes, which declined with time following abstinence. Such evidence shows that well studied hepatotoxins and surgical liver injury affect pathways of ammonia metabolism and suggests that urinary orotic acid can be an indicator of hepatotoxicity and increased needs for arginine. Arginine-deficient diets and alcohol feeding both enhance fatty deposition in the liver, which can be worsened by high fat intakes in rats. Alcoholism, various other diseases, and fasting and realimentation change orotic acid excretion. Such responses will have to be taken into account in establishing "normal values" for OA excretion.

Adult↗
PubMed1987

Effects of Triton WR 1339 and orotic acid on lipid metabolism in rats.

In order to investigate the effect of hepatic cholesterol flux on biliary bile acids, Triton WR 1339 and orotic acid were administered to rats, and the biliary cholesterol, phospholipids and bile acids were analyzed together with serum lipoproteins and hepatic lipids. Triton, which raised serum very low density lipoprotein and lipid levels and decreased serum high density lipoprotein liver lipid levels, increase the biliary cholic acid group/chenodeoxycholic acid group ratio (CA/CDCA) in the bile without affecting the total amount of bile acids and the other biliary lipids. Orotic acid, which decreased serum lipid and lipoprotein concentrations and increased liver lipid levels, increased the biliary excretion of cholesterol and phospholipids, but produced no significant change in the total amount of bile acids and in the CA/CDCA ratio in bile.

Animals↗
PubMed1998

Association between hepatic triacylglycerol accumulation induced by administering orotic acid and enhanced phosphatidate phosphohydrolase activity in rats.

Orotic acid is known to cause fatty liver, but it is unclear whether this is caused partly by stimulation of the enzymes for triacylglycerol (TG) synthesis. To understand the change of hepatic TG metabolism in fatty liver induced by orotic acid, we determined the liver tissue TG level and phosphatidate phosphohydrolase (PAP) activity over time in rats fed on a diet containing orotic acid (OA). A dietary lipid content of 10% was achieved by using n-6 fatty acid-rich corn oil in experiment 1, and n-6 fatty acid-rich safflower oil (SO) and n-3 fatty acid-rich fish oil (FO) with the same polyunsaturated fatty acid/monounsaturated fatty acid/saturated fatty acid (P/M/S) ratio in experiment 2. In experiment 1, an increase in the hepatic TG level due to OA intake was observed from day 5 onwards, the level rising approximately 6-fold by day 10. The activity of hepatic microsomal PAP, the rate-limiting enzyme in TG synthesis, increased markedly from day 5 onwards, concurrent with the liver diacylglycerol concentration. A strong correlation (r = 0.974) was observed between the hepatic TG level and microsome-bound PAP activity. In experiment 2, we investigated the effects of dietary fatty acid on OA-induced fatty liver. Compared with the n-6 fatty acid-rich vegetable oil diet, the relative increase in hepatic TG was smaller with the n-3 fatty acid-rich FO diet, and hepatic PAP activity fell markedly to the level for an OA-free diet. In addition, the hepatic TG accumulation and serum TG concentration were lower in the FO group than in the SO group. Nevertheless, because the hepatic TG level was low, it seems that the inhibition of liver PAP activity by FO possibly had a strong influence on the accumulation of TG in the liver. In conclusion, enhanced TG synthesis mediated by changes in liver PAP activity was involved in the hepatic TG accumulation induced by OA administration, this change being markedly suppressed by dietary n-3 fatty acids.

Animals↗
PubMed1982

A new method for measuring urinary orotic acid.

A relatively simple and specific method for measuring urinary orotic acid is reported. With this method, orotic acid is enzymatically converted to uridine 5-phosphate. The difference in absorbance produced by a simple colorimetric procedure in the presence and absence of the enzymatic conversion allows specific measurement of orotic acid. Normal values for urine are less than 4 micrograms/mg creatinine in infants and less than 3 micrograms/mg creatinine in older children and adults.

Adolescent↗
PubMed1975

Differential labeling with orotic acid and uridine in compensatroy renal hypertrophy.

Using [5-3H]orotic acid and [5-3H]uridine as precursors, we compared the efficiency of labeling and the localization of labeled RNA during compensatory hypertrophy of the mouse kidney. [5-3H]orotic acid in tubules labeled RNA 15 times more intensely that [5-3H]uridine, presumably because of greater incorporation of orotic acid into tubular cells. Of the orotic acid label, 97% was in tubular cells, mostly in the proximal tubules. Only about 80% of the uridine label was in the tubules; the ratio in proximal tubules compared with that in distal tubules was 2:1. No changes in distribution within the nephron were produced during compensatory hypertrophy. [5-3H]uridine should be used as the precursor of generalized labeling is desired, but [5-3H5orotic acid is the better precursor of RNA for many studies of compensatory hypertrophy since it is more efficient and concentrates in the segments of greatest biologic activity.

Animals↗
PubMed1984

Promotion by orotic acid of liver carcinogenesis in rats initiated by 1,2-dimethylhydrazine.

Our earlier experiments revealed that orotic acid, a precursor for pyrimidine nucleotides, selectively stimulated the growth of carcinogen-modified liver cells to grow into enzyme-altered hepatocytes (Cancer Lett., 16: 191-196, 1982). The present study was designed to determine whether prolonged feeding of orotic acid will result in hepatocellular carcinoma in initiated rats. Accordingly, groups of rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or an equivalent volume of 0.9% sodium chloride solution 18 hr after two-thirds partial hepatectomy. After 1 week of recovery, they were continued on either the basal diet or the basal diet containing 1% orotic acid for 10 to 13 months. Some groups of rats, in addition, received a single necrogenic dose of CCl4 8 weeks following exposure to orotic acid diet. The results obtained indicated that 87.5% of initiated rats exposed to orotic acid developed hepatocellular carcinomas in 10 months and 100% in 13 months. Initiated rats exposed to orotic acid diet coupled with a single administration of CCl4 developed 100% hepatocellular carcinoma by 10 months. In contrast, the incidence of hepatocellular carcinoma in initiated rats fed basal diet alone for 13 months was 37.5%, while, in those that received CCl4 in addition, the incidence was 25% in 10 months. Interestingly, a significant number of liver cancers (29 to 36%) in the orotic acid-fed group metastasized to lungs, whereas none of the liver cancers in rats exposed to basal diet metastasized.(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dimethylhydrazine↗
PubMed1982

Experimental electroencephalographic study on orotic acid.

Proceeding from the data obtained concerning the effects of orotic acid on excitability processes in CNS and our neuropharmacological investigations, we studied its effects on cerebral bioelectrical activity in acute experiments with "encéphale isolé" and in intact animals with chronically implanted electrodes, at single and 10-day treatment periods in a setting where the spontaneous activity and that evoked by visual and sound stimulation were recorded. At a dose of 100 mg/kg i.v. orotic acid significantly increased the theta wave range and showed a tendency towards increasing the beta waves, preserving, at a somewhat lower level (in comparison with control animals), the reactions to visual and sound stimulation. Comparison with the neuropharmacological studies is good reason to conclude that orotic acid stabilizes the cortical neuronal function; it does not influence the ascendent activating reticular formation, but probably inhibits the descending polysynaptic pathways. It is suggested that besides its metabolic effect orotic acid also has an effect on brain vessels.

Acoustic Stimulation↗
PubMed2005

Synthesis and properties of PNA oligomers containing orotic acid derivatives.

We have investigated the incorporation of C6-derivatives of uracil into polypyrimidine peptide nucleic acid oligomers (PNA). Starting with orotic acid (uracil-6-carboxylic acid) we have prepared a PNA monomer containing the methyl orotate nucleobase which is compatible with Fmoc-based synthesis. Treatment of the resin-bound oligomers with hydroxide or amines cleanly converted the ester to an orotic acid or orotamide-containing PNA. Alternatively, the methyl orotate-containing PNA was liberated from the resin by standard acidolysis. PNA bearing a modified nucleobase was found to hybridize to both poly(rA) and poly(dA). Complexes with poly(rA) were more stable than those with poly(dA) but both were destabilized relative to an unmodified PNA. Modification of a terminal residue was tolerated better than modification of an internal position. The type of charge provided by the modification affected the complex stability. In the worst case, an internal modification was nearly as detrimental as a base mismatch.

Base Composition↗