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PubMed2004

Comparison of ion-pair chromatography and capillary zone electrophoresis for the assay of organic acids as markers of abnormal metabolism.

The abnormal organic acids in urine are closely related with physiological metabolism. To determinate the low-molecular-mass metabolites in human biological fluids, although there were some previous reports by both of capillary electrophoresis and ion-exchange high-performance liquid chromatography, but it was rarely found by reverse phase of liquid chromatography using ion pair reagent. The objective of this study was aimed to suggest and compare two methods, an additional chromatographic method-ion-pair chromatography (IPC) and a sharp capillary zone electrophoresis (CZE), to determinate organic acids, acting as the abnormal metabolic markers, namely uric acid, orotic acid, pyruvic acid, alpha-ketoglutaric acid, fumaric acid, and hippuric acid. The proposed method of IPC possessed both the extreme stability for column and the good results of reproducibility, linearity and detection limit. The optimum mobile phase was 22% methanol and 10 mM tetra-n-butyl ammonium hydrogen sulfate (pH 4) by gradient elution. As well as the optimum condition of CZE was 5% acetonitrile and 0.5 mM CTAB in phosphate buffer. From the results, CZE showed better recovery and sharp lucid electropherogram. Finally, the two proposed analytical methods were applied to assay human urine with direct and spiked analysis. CZE showed good potency to overcome the sample-to sample variation with standard deviation less than 10%. By comparison results of urinary spiked analysis between IPC and CZE by statistical paired t-test, the results were evaluated no significant difference under P < 0.05. The quantitative linearity of both methods was fitted in application of clinical biological analysis even with 50-fold dilution.

Acids↗
PubMed1980

Orotic acid-induced metabolic changes in the rat.

The effects of orotic acid consumption on hepatic lipid and nucleotide metabolism were examined concurrently in the rat. When orotic acid was fed at 1.0%, fatty liver development was evident by day 7 but not by day 3, whereas a decreased purine/pyrimidine ratio of hepatic acid-soluble nucleotides was noted by day 3. As nucleotide changes preceded hepatic fat accumulation, they could be a contributing factor in the etiology of fatty liver. When fed for 10 days, rats did not accumulate hepatic fat on a diet containing 0.1%, but did on 0.5 and 1.0%; similarly, the purine/pyrimidine ratio was not significantly affected on 0.1% but was decreased on both 0.5 and 1.0% orotic acid. These results indicate that orotic acid alters both hepatic lipid and nucleotides when consumed by rats at a level above 0.1%. As measured in these studies, hepatomegaly did not always accompany hepatic steatosis and appeared to be a subsequent development. In addition, L-dihydroorotate was shown to be as effective as orotic acid in increasing hepatic weight and lipid whereas uridine was ineffective.

Animals↗
PubMed1991

Biochemical and immunohistochemical analysis of orotic acid-induced fatty liver.

Orotic acid-induced fatty livers were examined by biochemical and immunohistochemical approaches. Lipid peroxide levels by the thiobarbituric acid method and glutathione-peroxidase (GSH-PO) activity in the liver homogenates from orotic administered rats were similar to those of controls. Immunohistochemical localization of GSH-PO in orotic acid-induced fatty liver was mainly observed in the portal zone of the hepatic lobules. This staining pattern of GSH-PO was similar to that of the controls. No remarkable changes in GSH-PO staining patterns were detected in orotic acid-induced fatty liver. Our data strongly suggested that no lipid peroxidation is actively involved in the genesis of fatty liver due to the administration of orotic acid, and GSH-PO a protective enzyme against lipid peroxidation, was not inhibited by orotic acid-induced fatty liver.

Animals↗
PubMed1983

Mutagenicity of hydrazides of pyrimidine-nucleotide-precursors in the Salmonella-oxygenase test.

Five newly synthesized hydrazides: L-aspartic acid dihydrazide, DL-ureido-succinic acid dihydrazide, DL-dihydroorotic acid hydrazide, orotic acid hydrazide, and 2,2'-anhydro-1-(beta-D-arabinofuranosyl)-orotic acid hydrazide were tested for mutagenicity in the Ames test. All these hydrazides except DL-ureidosuccinic acid dihydrazide were found to be non-mutagenic. The mutagenic activities of the latter compound which causes base-pair substitution was decreased in the presence of metabolic activator.

Animals↗
PubMed1988

Enzyme histochemical and ultrastructural approach in orotic acid-induced fatty liver and their recovery process in Wistar rats.

Fatty liver was induced in Wistar rats by orotic acid and the recovery process was studied by enzyme histochemical staining for non specific esterase, lipase and by ultrastructural investigation. Enzyme histochemically, these enzyme activities were markedly decreased in orotic acid-induced fatty liver. However, during the recovery process after the end of orotic acid administration, these enzyme activities clearly appeared. Under these conditions, no significant ultrastructural alterations could be detected. Based on our data, pathogenesis of orotic acid-induced fatty liver was discussed.

Animals↗
PubMed1986

Nascent high density lipoproteins from liver perfusates of orotic acid-fed rats.

Uniformly fatty livers from orotic acid-fed rats secreted almost no very low density lipoproteins (VLDL) but normal amounts of nascent high density lipoproteins (HDL) accumulated in perfusates. When lecithin:cholesterol acyltransferase (LCAT) was inhibited, nascent HDL were uniformly discoidal and lacked cholesteryl esters. Lipid and apoprotein compositions of nascent HDL from normal and fatty livers were similar whether LCAT was inhibited or not. Apolipoprotein B-100 was not detected in perfusates of uniformly fatty livers, but small amounts of apolipoprotein B-48 were present in HDL2 fractions. Nascent lipoproteins were not seen in Golgi compartments, but lipid-rich particles were clearly evident in endoplasmic reticulum cisternae adjacent to the cis face of the Golgi complex, suggesting that orotic acid blocks VLDL secretion by preventing translocation of nascent particles from the endoplasmic reticulum to the cis Golgi compartment. The accumulation of normal amounts of discoidal HDL in liver perfusates despite virtual absence of triglyceride-rich lipoproteins in Golgi secretory compartments, the space of Disse, and the perfusate is inconsistent with the concept that nascent HDL are exclusively a product of surface remnants cast off during lipolysis of chylomicrons and VLDL.

Administration, Oral↗
PubMed1971

Serum lipoprotein accumulation in the livers of orotic acid-fed rats.

This study provides confirmation of previous observations that showed that rats fed a diet containing 1% orotic acid for 7 days develop a fatty liver and that there is an inhibition of the secretion of low density lipoproteins without altering general liver protein synthesis. Accumulated fat droplets (liposomes) are entrapped within rough endoplasmic reticulum vesicles. In this study, these vesicles have been shown to accumulate the apolipoproteins of low and very low density lipoproteins. Inhibition of lipoprotein secretion was demonstrated by perfusion of livers from orotic acid-fed rats with a serum-free medium. Liposomes were isolated from these rats. Partially delipidated liposomes, but not similarly treated microsomes or cell sap, were found to form a precipitation line when reacted against anti-low density lipoprotein antiserum. Detergent solubilization of the liposome followed by density gradient centrifugation resulted in a peak at d 1.025 g/ml containing both lipid and protein. Acrylamide electrophoresis in 8 m urea after total delipidation demonstrated liposomal bands which coelectrophoresed with three of four very low density lipoprotein bands; there was no band corresponding to the very low density lipoprotein band which travels furthest in acrylamide electrophoregrams. However, acrylamide electrophoresis of the apoproteins of serum high density lipoprotein from orotic acid-fed animals revealed the presence of the latter band. The results indicate that liver liposomes from orotic acid-fed rats apparently contain the low density apoprotein and probably several other very low density lipoprotein peptides.

Animals↗
PubMed1986

Ultrastructural and enzyme histochemical studies in orotic acid-induced fatty liver.

To confirm the relationship between fatty changes and zonal distribution in the hepatic lobules, we studied the ultrastructural and enzyme histochemical alterations in rat hepatocytes of orotic acid which blocks the release of lipoproteins, administered for 7 days, fatty changes were clearly detected in the hepatocytes, but no zonal distribution of fat in the hepatic lobules was detected. The most striking ultrastructural alterations were observed in the rough endoplasmic reticulum and Golgi complexes. The intensity of the staining of non-specific esterase and lipase was markedly decreased. Based on these data, functional aspects of the hepatocytes in orotic acid administration were discussed.

Animals↗
PubMed1977

Reversal of orotic acid-induced fatty liver in rats by clofibrate.

The addition of 1 per cent orotic acid to a sucrose-enriched semipurified diet results in markedly fatty liver when fed to rats for 7 to 22 days. Light microscopy reveals lipid droplets, mostly small, distributed throughout the cytoplasm of all hepatocytes. Electron microscopy shows that all the endoplasmic reticulum (ER) is broken into vesicles. Within the interior (cisterna) of each vesicle one or more lipid droplets are present. Morphologic signs of normal lipid transport (ER to Golgi apparatus to space of Disse) disappear: the Golgi elements are flattened and lack very low density lipoproteins particles; the Golgi-derived secretory vacuoles are not present. Biochemical analyses show an increase in hepatic triacylglycerol levels, to approximately 8 times the levels of sucrose-fed controls by the 7th day, 18 times by the 15th day, and 25 times by the 22nd day. Hepatic cholesterol levels increase, 2- to 4-fold. Serum triacylglycerol levels fall markedly; serum cholesterol levels are reduced. Immunoelectrophoretic determinations show that the apoprotein B component of plasma lipoproteins is practically absent at 7 days and increases slightly at 22 days. Reversal of an orotic acid-induced fatty liver is achieved by adding ethyl chlorophenoxyisobutyrate (clofibrate or CPIB) to the diet. By 8 to 16 days the ER of the hepatocytes returns to its usual parallel configuration and lipid droplets are not seen within its cisternae. Morphologic features of normal lipid transport reappear. GERL becomes prominent, distended with small particles, interpreted as lipid undergoing degradation. Lipid-containing residual bodies are common. Peroxisomes are more numerous than in hepatocytes of control rats. Liver triacylglycerol levels approach sucrose-fed control levels, and serum triacylglycerol levels return to chow-fed control levels. Hepatic cholesterol levels are similar to those of sucrose-fed and chow-fed controls, whereas serum cholesterol levels are lower. Serum apoprotein B levels return to chow-fed control levels. A sequence of events terminating in the removal of lipid from the hepatocytes is suggested by observation of morphologic changes following chlorophenoxyisobutyrate administration. This appears to involve transport of lipid into the cytosol where it accumulates as large spheres. Extensive accumulations of smooth ER appear. The cytosol lipid then disappears as the rough ER develops. Peroxisomes and mitochondria are prominent during the reversal process.

Animals↗
PubMed1994

Resistance of hepatic nodules to orotic acid-induced accumulation of uridine nucleotides.

It has been hypothesized that orotic acid (OA) promotes rat liver carcinogenesis by a differential mitoinhibitory mode. Consistent with this hypothesis, hepatic nodules are relatively resistant to OA-induced mitoinhibition. OA-induced mitoinhibition is dependent on the metabolism of OA to uridine nucleotides. The present studies investigate the uptake and metabolic pathway of OA, both in vivo and in vitro, as a possible basis for the resistance of hepatic nodules to OA-induced mitoinhibition. Rats bearing hepatic nodules exposed to 1% dietary OA exhibited increased levels of uridine nucleotides in the surrounding non-nodular liver (from 0.44 to 0.70 mg/g liver) but not in the hepatic nodules. Further, following administration of [3H]OA i.p., nodules have significantly lower levels of acid-soluble radioactivity compared to the non-nodular surrounding tissue. Furthermore, most of the acid-soluble radioactivity was present as uridine nucleotides, suggesting that the OA taken up was converted to uridine nucleotides. Similarly, hepatocytes from nodules in primary culture incubated with radiolabeled OA, have significantly lower levels (46-60%) of acid-soluble radioactivity. These results suggest that the decreased uptake of OA by hepatic nodules may be a factor contributing to the observed resistance of hepatic nodules to the mitoinhibitory effects of OA.

Animals↗
PubMed1999

Urinary orotic acid-to-creatinine ratios in cats with hepatic lipidosis.

OBJECTIVE: To determine urinary orotic acid (OA) concentration and evaluate the urinary OA-to-creatinine ratio (OACR) in cats with hepatic lipidosis (HL). ANIMALS: 20 cats with HL and 20 clinically normal cats. PROCEDURE: Hepatic lipidosis was diagnosed on the basis of clinical signs, results of serum biochemical analyses, exclusion of other concurrent illness, and cytologic or histologic evaluation of liver biopsy specimens. Urine samples were collected from each cat and frozen at -20 C until assayed. Urine creatinine concentrations were determined, using an alkaline picrate method followed by spectrophotometric assay. Urine OA concentration was determined, using high-performance liquid chromatography. Minimum amount of detectable OA in feline urine was 1 microg/ml. Because of small interfering peaks near the base of the OA peak, the minimum quantifiable concentration of OA was determined to be 5 microg/ml. Urinary OACR was compared in both groups of cats. RESULTS: Differences in urinary OACR were not detected between clinically normal cats and cats with HL. Peaks were not detected for urinary OA in any of the 20 clinically normal cats. Of the 20 HL cats, 14 did not have detectable peaks for urinary OA. Of the 6 HL cats that had detectable urinary OA peaks, 3 had values of <5 microg/ml. CONCLUSIONS: Apparently, OACR does not increase significantly in cats with HL. CLINICAL RELEVANCE: Urinary OACR is not a useful diagnostic test for HL in cats.

Animals↗
PubMed1981

Species specificity of arginine deficiency-induced hepatic steatosis.

Hepatic steatosis resulting from the consumption of an arginine-deficient diet in the rat was found to occur independent of age or size. The rate of lipid biosynthesis as indicated by in vitro incorporation of 14C-acetate was significantly increased in rats fed an arginine-deficient diet when expressed per milligram liver. Supplementation of the arginine-deficient diet with 1% ribose, 1% hypoxanthine or 0.2% adenine depressed the fatty infiltration caused by arginine deficiency. Inosine, xanthine or uracil supplementation did not significantly alter the fatty infiltration, liver orotic acid biosynthesis or urinary orotic excretion induced by the arginine deficiency. Increased orotic acid excretion was also observed in the mouse, hamster and rabbit fed a diet devoid of arginine. However, consumption of the, arginine-deficient diet for 21 days did not significantly alter the liver lipid content of mice, hamsters or rabbits. Although the fatty infiltration appears to be limited to the rat, altered liver nucleotides were observed in rats, hamsters and rabbits fed an arginine-deficient diet. Similarities of arginine deficiency and orotic acid feeding in various species are discussed.

Age Factors↗
PubMed1996

Cryptogenic hepatitis masking the diagnosis of ornithine transcarbamylase deficiency.

We describe three children with transaminase elevations and hepatic insufficiency who were given the diagnosis of cryptogenic hepatitis after the more common viral and metabolic diseases of the liver had been excluded. However, further laboratory investigations showed hyperammonemia, low blood urea levels, elevated plasma glutamine levels, and low citrulline levels. Urinary excretion of orotic acid was higher than normal, with absent urinary homocitrulline and normal fractional tubular reabsorption of lysine, ornithine, and arginine. These findings suggest the diagnosis of ornithine transcarbamylase deficiency. We emphasize the importance of investigating possible urea cycle disorders by determining ammonia plasma levels, both at baseline and after a protein load; urinary and plasma amino acids; and urinary orotic acid in all patients with liver disease of indeterminate etiology.

Absorption↗
PubMed1969

Isolation and characterization of low density structures from orotic acid-induced fatty livers.

Centrifugation of a sucrose homogenate of the livers of female albino rats fed a 1.5% orotic acid diet for 3 wk yielded a pellicle containing low density structures. In morphology and biochemical properties these structures resembled those portions of endoplasmic reticulum which accumulated lipid. Electron microscopy indicated large droplets of lipid bounded by a membrane with attached ribosome-like particles. The presence of ribosomes in these structures was established by treatment with deoxycholate and centrifugation. The proportion of 18S and 29S RNA was the same as that found in the ribosomes from normal liver; however, the distribution of radioactivity between the 18S and the 29S RNA after injection of 8-(14)C-adenine was distinctly different. The RNA isolated from these structures contained a higher guanylic acid to cytidylic acid ratio than that found in the microsomes of the normal liver. It is proposed that these low density structures may be those portions of the endoplasmic reticulum in which there exists a defect responsible for the block in the assembly or secretion of plasma lipoprotein.

Adenine↗
PubMed1980

Effect of dietary arginine level on urinary orotate and citrate excretion in growing kittens.

Three experiments were conducted to examine the effect of dietary arginine on urinary orotic acid excretion and the relationship between orotic aciduria and the cat's dietary arginine requirement. In the first experiment, diets containing 1.66 or 0.83% arginine were compared for their ability to sustain growth and food intake and prevent orotic aciduria. Growth and food intake were similar for each diet but the cats fed the 0.83% arginine excreted seven times as much orotic acid as those fed the 1.66% arginine. In the second experiment, diets containing 0.2, 0.4, 0.6, 0.8 and 1.0% arginine were compared for their ability to support growth and food intake and to prevent citric and orotic aciduria. Growth and food intake were optimized with arginine as 0.8% of the diet. Over the range of 0.4--1% arginine, orotic acid excretion was inversely related to the level of arginine, also orotate excretion of cats fed all levels of arginine was greater than that recorded in cats given 1.66% dietary arginine. The estimated level of dietary arginine required to minimize orotic acid excretion was 1.05%, which is 0.3% in excess of that required for maximum growth. Citrate excretion did not respond to dietary arginine level. In the third experiment, cats receiving a commercial cat food containing 1.74% arginine did not show orotic aciduria.

Aging↗