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PubMedDate not supplied

[Effect of potassium orotate on metabolism in chickens under different provision with vitamin D3].

Vitamin D3 induction of the vitamin-D3-dependent proteins biosynthesis and certain indexes characterizing the rachitic state in animals were studied as affected by potassium orotate. Introduction of potassium orotate to the rachitogenic diet in combination with vitamin D3 is shown to normalize the processess of bone mineralization and to increase intensity of chicken growth. In duodenum mucosa with rachitis orotate normalizes the activity of alkaline phosphatase, raises the content of calcium-binding protein and stimulates the latter formation after administration of vitamin D3; orotate favours redistribution of the purine and pyrimidine nucleotides content. Radioactive orotic acid is subjected to intensive metabolism in mucosa and is converted to nucleotides of pool and RNA.

Animals↗
PubMed1995

The sparse fur mouse as a model for gene therapy in ornithine carbamoyltransferase deficiency.

The sparse fur (spf/Y) mouse was evaluated as a model for studying gene therapy in ornithine carbamoyltransferase deficiency (OCTD), the most common inborn error of urea synthesis. Previous studies have defined a number of biochemical characteristics of this animal model that are analogous to the human disease: OCTD in liver, elevated ammonium and glutamine, low citrulline and arginine in plasma, elevated urinary orotic acid excretion, neurochemical alterations and responsiveness to alternative pathway therapy. In this study, metabolic flux, survival, behavior and learning of these animals were examined in preparation for a trial of gene therapy. We found that, as has been previously reported, OCT activity in liver ranged from 10 to 20% of control. Yet, stable isotope studies using 15N ammonium chloride to follow ureagenesis in vivo showed 55% of normal urea synthetic capacity. This suggests that partial correction with gene therapy may be sufficient to normalize urea synthesis. Although it has been suggested that liver OCTD and its consequent metabolic effects normalize without treatment by adulthood in the spf/Y mouse, we did not find this to be the case. We documented that the spf/Y mouse had a markedly decreased lifespan (< 10% of normal) and remained runted throughout life. In terms of behavior, the spf/Y mice had evidence of decreased learning in a passive avoidance task that was not attributable to alterations in activity. These clearly definable metabolic and behavioral abnormalities suggest that the spf/Y mouse should prove a useful model for studying the efficacy of gene therapy in OCTD.

Amino Acid Metabolism, Inborn Errors↗
PubMed1966

The relationship between cellular nucleic acids in the developing rat cerebral cortex.

1. In the rat cerebral cortex net DNA synthesis ceases when the animal has reached about 25g. body weight (18 days of age). There is then little further change in the DNA content per cortex. 2. Nuclear and transfer RNA follow a similar pattern to DNA. 3. Microsomal and ribosomal RNA content increases up to 25g. body weight but then declines. The decrease in ribosomal and microsomal RNA content is associated with a change in RNA base composition. 4. Incorporation of [(14)C]orotic acid into nuclear RNA proceeds at a similar rate in 4-day-old and adult animals. However, there is a lag period of about 60min. in the young animals during which incorporation into the ribosome fractions proceeds slowly. In the adult animals the lag period is not seen.

Adenine↗
PubMed1993

Induction of hepatic nodules in the rat by aristolochic acid.

Aristolochic acid (AA), used as an anti-inflammatory agent in the past, is known to be mutagenic and carcinogenic to several organs of the rat, including forestomach, renal pelvis and urinary bladder. However, despite the induction of DNA adducts in the liver, no carcinogenic potential of AA has been reported in the latter organ. The present study was based on the rationale that the lack of carcinogenicity of AA to the liver could be because this chemical may not be necrogenic at the doses examined and liver cell proliferation has been established as an essential component for initiation of liver carcinogenesis in the rat. The results indicated that AA is non-necrogenic to the rat liver. However, a single non-necrogenic dose of AA (10 mg/kg b.w., i.p.) given 18 hours after 2/3 partial hepatectomy initiated liver cell carcinogenesis. The initiated cells are promotable with 1% dietary orotic acid, a liver tumor promoter, to form glutathione-S-transferase 7-7 positive hepatic foci and nodules.

Animals↗
PubMed1985

Effects of gomisin A on liver functions in hepatotoxic chemicals-treated rats.

The effects of gomisin A, which is a lignan component of schizandra fruits, on liver functions in various experimental liver injuries and on bile secretion in CCl4-induced liver injury were studied. Gomisin A weakly accelerated the disappearance of plasma ICG by itself at a high dose (100 mg/kg, i.p.). All of the hepatotoxic chemicals used in this study inhibited the excretion of ICG from plasma. Gomisin A showed a tendency to prevent the delays of the disappearance of plasma ICG induced by CCl4, d-galactosamine and orotic acid, but not that by ANIT. Bile flow and biliary outputs of total bile acids and electrolytes (Na+, K+, Cl- and HCO3-) were decreased in CCl4-treated rats. Gomisin A maintained bile flow and biliary output of each electrolyte nearly to the level of the vehicle-treated group, but did not affect biliary output of total bile acids. These findings suggest that gomisin A possesses a liver function-facilitating property in normal and liver injured rats and that its preventive action on CCl4-induced cholestasis is due to maintaining the function of the bile acids-independent fraction.

1-Naphthylisothiocyanate↗
PubMed2000

Fluoroorotic acid-selected Nicotiana plumbaginifolia cell lines with a stable thymine starvation phenotype have lost the thymine-regulated transcriptional program.

We have selected 143 independent Nicotiana plumbaginifolia cell lines that survive in the presence of 5-fluoroorotic acid. These lines show several diverse phenotypes. The majority of these cell lines showed reduced levels of UMP synthase. However, one particular phenotype, which represents 14% of the total independent lines (20 cell lines), showed an unexpected, high level of UMP synthase and was therefore analyzed in detail. The selected cell lines showed no differences with wild-type cells with respect to uptake of orotic acid, affinity of UMP synthase for its substrates, or UMP synthase gene-copy number. Alternative detoxification mechanisms were also excluded. The elevated enzyme activity was correlated with elevated UMP synthase protein levels as well as elevated UMP synthase mRNA levels. In contrast to wild-type cell lines, the fluoroorotic acid-selected cell lines did not respond to thymine or to other biochemicals that affect thymine levels. In addition, there was also a concomitant up-regulation of aspartate transcarbamoylase, however, dihydroorotase and dihydroorotate dehydrogenase are not up-regulated in these cell lines.

Aspartate Carbamoyltransferase↗
PubMed1998

The addition of oat fiber and natural alternative sweeteners in the manufacture of plain yogurt.

Calorie-reduced yogurts that were fortified with 1.32% oat fiber were prepared from lactose-hydrolyzed milk, alone and supplemented with 2 and 4% sucrose or with 1.6, 3.6, and 5.5% fructose. Treated samples were compared with unsweetened yogurt and with yogurts sweetened with 2, 4, and 6% sucrose. Addition of 5.5% fructose increased fermentation time by 60%, slowing down the production of lactic, pyruvic, acetic, and propionic acids and the consumption of hippuric and orotic acids. Lactose hydrolysis had an inhibitory effect on starter activity at the beginning of fermentation and a stimulatory effect at the end of fermentation. Fiber addition led to increases in concentrations of acetic and propionic acid. Lactobacilli counts were lower in samples treated with fructose. The use of hydrolyzed milk had a stimulatory effect on total bacteria and lactobacilli counts throughout the cold storage period. After 28 d of storage, lactobacilli counts were consistently higher in fiber-fortified yogurts, but total bacteria counts were lower. Apparent viscosity increased with the addition of sweetener and fiber. Lactose-hydrolyzed and fructose yogurts had the highest viscosity values. Samples sweetened with sucrose received the highest scores for flavor. Fiber addition decreased overall flavor quality. The lactose-hydrolyzed yogurts received the highest flavor scores, independent of fiber fortification. Fiber addition improved the body and texture of unsweetened yogurts but lowered overall scores for body and texture in yogurts sweetened with sucrose.

Animals↗
PubMed1981

[Hyperammonemia in the newborn through ornithine transcarbamylase deficiency (author's transl)].

This is a report of a family with hyperammonemia in the newborn, very probably due to ornithine transcarbamylase deficiency. Typically the male infant died in the newborn period within 74 hours. In the female newborn it was possible to provide a normal development with protein restricted diet. In mother's line there are unexplained death's of infants. The examination of amino acids and organic acids excluded other disturbances. The determination of orotic acid in the urines and oral loading with protein indicated to OTC-deficiency. The RDS-symptomatic and pulmonary bleeding in the newborns with hyperammonemia is emphasized.

Ammonia↗
PubMed1968

Effect of denervation on the synthesis of ribonucleic acid and deoxyribonucleic acid in rat diaphragm muscle.

1. The effect of unilateral denervation of rat diaphragm muscle on its content of nucleic acids and their incorporation of precursors was investigated. 2. After denervation the paralysed hemidiaphragm hypertrophies and within 3 days its content of RNA increases considerably. The concentration of DNA/unit mass remains fairly constant. 3. During this period there is some increase in the rate of incorporation of [(14)C]adenine into RNA, whereas there is some diminution in the rate of incorporation of [(14)C]orotic acid. 4. Incorporation of [(14)C]adenine and [(3)H]thymidine into DNA is much increased in the paralysed tissue, reaching its maximum by about the third day, but returning to normal by the tenth. 5. The significance of these results in relation to the hypertrophy after denervation is discussed.

Adenine↗
PubMed1970

Co-ordination between membrane phospholipid synthesis and accelerated biosynthesis of cytoplasmic ribonucleic acid and protein.

1. The rate of synthesis of membrane phospholipid was studied in rat liver and seminal vesicles by following the incorporation of [(32)P]orthophosphate, [(14)C]choline and [(14)C]glycerol. Particular emphasis was laid on the endoplasmic reticulum, which was fractionated into smooth microsomal membranes, heavy rough membranes, light rough membranes and free polyribosomes. 2. Phospholipid labelling patterns suggested a heterogeneity in the synthesis and turnover of the different lipid moieties of smooth and rough endoplasmic membranes. The major phospholipids, phosphatidylcholine and phosphatidylethanolamine, were labelled relatively rapidly with (32)P over a short period of time whereas incorporation of radioisotope into the minor phospholipids, sphingomyelin, lysolecithin and phosphatidylinositol proceeded slowly but over a longer period of time. 3. The incorporation of orotic acid into RNA and labelled amino acids into protein of the four submicrosomal fractions was also studied. 4. Rapid growth of the liver was induced by the administration of growth hormone and tri-iodothyronine to hypophysectomized and thyroidectomized rats and by partial hepatectomy. Growth of seminal vesicles of castrated rats was stimulated with testosterone propionate. 5. The rate of labelling of membrane phospholipids was enhanced in all major subcellular particulate fractions (nuclear, mitochondrial and microsomal) during induced growth. However, it was in the rough endoplasmic reticulum that the accumulation of phospholipids, RNA and protein was most marked. The effect of hormone administration was also to accelerate preferentially the labelling with (32)P of sphingomyelin relative to that of phosphatidylcholine or phosphatidylethanolamine. 6. Time-course analyses showed that, in all four growth systems studied, the enhancement of the rate of membrane phospholipid synthesis coincided with the rather abrupt increase in the synthesis of RNA and protein of the rough endoplasmic reticulum. Growth hormone and tri-iodothyronine administered to hypophysectomized rats had additive effects in all the biosynthetic processes. The latent period of action of each hormone was maintained so that two waves of proliferation of endoplasmic reticulum occurred if the hormones were administered simultaneously. 7. It is concluded that there is some mechanism in the cell that tightly co-ordinates the formation of membranes, especially those of the endoplasmic reticulum, when an increased demand is made for protein synthesis.

Amino Acids↗
PubMed1986

Arginine needs, physiological state and usual diets. A reevaluation.

Evidence is discussed that puts in question the widely held belief that adult mammals, including human beings, can meet all of their arginine needs by endogenous synthesis. Arginine, used in synthesis of body proteins, is essential for ammonia detoxification via urea synthesis, which prevents metabolic derangements caused by elevations in tissue ammonia. It is a precursor for polyamine synthesis and is the only source of amidino groups for the formation of creatine, a major source of high energy phosphate for regeneration of ATP in muscle. Arginine at supraphysiologic doses is thymotropic and a secretagogue for hormones that control growth and metabolism. Studies in mature rats show that glucose tolerance, the rate of repletion from severe protein undernutrition and recovery from trauma are significantly accelerated by dietary arginine. Oral or intravenous administration of excessive arginine reverses nitrogen loss and immune suppression after trauma in rats, and healthy human volunteers consuming 30 g of oral supplements or arginine have shown significantly enhanced immunoreactivity of the lymphocytes of their peripheral blood. Calculations based on creatinine excretion show that 0.8 g of protein/kg body weight of the quality supplied by the usual American diet barely provides sufficient arginine for synthesizing the quantity of creatinine excreted daily in the urine of 70-kg adults. Human patients who often consume less than this amount of protein show a decline in creatinine excretion during illness; the decrease suggests that their intake of arginine is less than optimal. Recent studies of intraspecies and interspecies differences in responses to arginine reemphasize that dispensability or indispensability of arginine is a matter of definition and that growth and nitrogen balance data impose significant limitations on the drawing of far-reaching conclusions about the needs for arginine by mammalian adults including humans. Orotic acid excretion, immune responsiveness and circulating hormone levels are measures that should be evaluated for identifying when enhancement of arginine intakes might prove beneficial.

Animals↗
PubMedDate not supplied

[Activity of protein-synthesizing system and RNA synthesis in the liver and spleen of rats in stress caused by burns].

Period of decreased protein synthesis was observed in rats within first hours, after burns but later on the synthesis was distinctly increased in liver and spleen tissues. This increase was apparently due to induction of RNA synthesis as actinomycin D removed the effect of burns on the protein synthesis. Immediately after the burns incorporation of 14C-orotic acid into rapidly-lebelling RNA of rat liver tissue was increased; the increased RNA synthesis was observed and at the 3-rd day after burns.

Albumins↗
PubMed1975

[Inhibition of the incorporation of tritiated thymidine in fetal rat liver in cell culture by a fractioned liver extract].

A dialyzed rat liver extract has been chromatographed on "Sephadex G 25" and then on "Sephadex G 50". Thus we found a fraction which inhibits the incorporation of tritiated thymidine and stimulates the incorporation of labelled orotic acid into foetal rat liver cells in culture, but has no effect on DNA synthesis in cell lines derived from lymphocytes and fibroblasts.

Animals↗
PubMed1968

Murine hepatitis virus: effect on liver RNA.

After infection of mice with hepatitis virus MHV3, the RNA in the liver undergoes changes. The fraction extracted with phenol at 0 degrees C does not alter. However, the fraction extracted with hot phenol at elevated pH (60 degrees C, pH 8.3) shows a 16S peak on sucrose-density-gradient centrifugation. This fraction shows actinomycin D-resistant incorporation of C(14)-orotic acid in infected but not in control livers-possible evidence of the RNA nature of MHV3.

Alanine Transaminase↗
PubMed1995

The crystal structure of the orotate phosphoribosyltransferase complexed with orotate and alpha-D-5-phosphoribosyl-1-pyrophosphate.

The three-dimensional structure of Salmonella typhimurium orotate phosphoribosyltransferase (OPRTase) in complex with the ribose 5-phosphate donor alpha-D-5--phosphoribosyl-1-pyrophosphate (PRPP) and the nitrogenous base orotic acid has been solved and refined with X-ray diffraction data extending to 2.3 A resolution to a crystallographic R-factor of 18.7%. The complex was generated by carrying out catalysis in the crystal. Comparison of this structure with the previously reported structure of the orotidine 5'-monophosphate (OMP) complex [Scapin, G., Grubmeyer, C., and Sacchettini, J. C. (1994) Biochemistry 33, 1287-1294] revealed that the enzyme backbone undergoes only small movements. The most significant differences occur near the active site, at Ala71-Gly74, with the largest difference involving the side chains of Lys73, Val127-Ala133, the 5'-phosphate binding loop, and a long, solvent-exposed loop at the dimer interface. The position of the ribose moiety is, on the other hand, very different in the OMP and PRPP.orotate complexes, with its anomeric carbon moving approximately 7 A across the binding cavity. In the PRPP.orotate complex the highly conserved acidic side chain of Asp124 interacts with the ribose of PRPP, whereas there are no interactions of this aspartate with the substrate in the OMP complex.

Binding Sites↗
PubMed1976

The effect of the number of daily training sessions on skeletal muscle protein synthesis.

The purpose of this investigation was to examine the effects of training either once or three times/day on the principal stages of skeletal muscle. The experiments were carried out on male albino rats fed either 3 or 5 times/day a diet containing 20% protein. Experimental animals swam either once or 3 times/day, 6 days/week for 10 weeks with weights attached. The total duration of daily activity was equal for both groups and at 10 weeks each animal was swimming for 60 min/day with 3% of his body weight attached. All the animals were examined at rest after the 10-week training programs. The adequacy of the weight-loading and training schedules was estimated by body weight dynamics and such energy metabolites as creatine phosphate and glycogen. Skeletal muscle RNA and protein synthesis were studied by means of 14C-orotic acid and 14C-leucine incorporation, respectively. Quadriceps and gastrocnemius muscles were used for analysis in all experiments. It was found that the increase in the number of daily training sessions resulted in an increased content and intensity of synthesis of skeletal muscle proteins as evidenced by an increase in the content of amino acids in the muscle, an increased synthesis of both microsomal and ribosomal RNA, an increased stability of (poly-A)-containing messenger RNA, and an increased synthesis of all skeletal muscle protein fractions: myofibrillar, sarcoplasmic, and myostromal.

Animals↗
PubMedDate not supplied

[Properties of replicating DNA in the regenerating rat liver isolated during phenol fractionation].

Using phenol fractionation in the absence of detergents three DNA fractions differing by the incorporation of radioactive thymidine after pulse label are obtained from regenerating rat liver cells. Two fractions extracted under variety of conditions represent the main bulk of cell DNA (85--90%). DNA non-extractable under conditions used (DNA III) incorporates labelled thymidine 10--15 times faster than the first two DNA fractions. DNA III purified from the interphase layer by pronase, sodium dodecylsulfate and phenol sediments at 26S and has a hyperchromic effect about 40% after alkaline denaturation. Alkaline sucrose density gradient centrifugation of pulse-labelled DNA III revealed that nascent DNA consisted of heterogeneous fragments similar in size to the replication fragments in bacterial cells (9--10S). It was shown by CsCl equilibrium centrifugation that buoyant density of heat denatured DNA III labelled for 5 min with [3H]thymidine is heavier than the bulk of DNA prelabelled for 2 h with [14C]thymidine. After hydrolysis with RNase or alkali, buoyant densities of both DNAs became the same. These results support the idea of initiating role of RNA in the synthesis of discontinuous replicating fragments in regenerating rat liver cells. Specific radioactivity of RNA associated with replication fragments which are labelled for 5 min with [14C] orotic acid is 20 times more than of the same RNA labelled for 30 min. These data demonstrate high metabolic activity of initiating RNA.

Animals↗