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PubMedDate not supplied

[Incorporation in vivo of 14C-precursors into pyrimidine nucleotides of chicken liver and spleen tissues].

Maximum incorporation of the label after administration of 14C-bicarbonate to free pyrimidine nucleotides begins by the 60th minute. Radioactivity of cytidine nucleotides at all time points is four-eight times as low as that of uridine nucleotides. 2-14C-orotic acid is incorporated into acid-soluble nucleotides and RNA of the liver and spleen tissues. 60 min after administration of the isotope 20% of radioactivity was found in the liver and 0.3% in the spleen, in both tissues radioactivity of RNA is 20% of 14C-radioactivity in the acid-soluble fraction. The formation rate for cytidine nucleotides from uridine ones in the liver and spleen tissues is low, about 2-6% of uridine nucleotides radioactivity is found in them only, that may be due to a low activity of CTP-synthetase. The content of cytidine nucleotides in these organs is three-life times as low as compared to uridine nucleotides.

Animals↗

PubMedDate not supplied

[Mechanism of action of a novel antitumor preparation of chlofiden. Effect on RNA synthesis].

Study of the influence of the antitumor preparation chlofiden on RNA synthesis by sarcoma 45 and liver cells was carried out using 14C-orotic acid. Chlofiden was shown to activate RNA transport from the nucleus to the cytoplasm, and to reduce label incorporation into the nuclear and cytoplasmic RNA. Chlofiden increased the rate of RNA processes, which promoted some increase of label incorporation into low molecular RNA fraction of the nucleus and the cytoplasm. High and stable antitumor activity of chlofiden on sarcoma 45 was established.

Animals↗

PubMed1990

Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women.

Ornithine carbamoyltransferase is an X-linked mitochondrial enzyme expressed in hepatocytes and enterocytes. A deficiency of this enzyme results in central nervous system dysfunction, which may be fatal in newborn boys. Milder forms are seen in older boys and girls and in adults. Establishing the carrier status of women at risk for ornithine carbamoyltransferase deficiency is important for determining reproductive and medical risks for affected women. We report a test to establish the carrier status of women at risk for ornithine carbamoyltransferase deficiency. This test relies on the allopurinol-induced accumulation of orotidine, whose synthesis is stimulated by carbamoyl phosphate, a substrate that accumulates in ornithine carbamoyltransferase deficiency. We used anion-exchange, high-performance liquid chromatography to measure urinary orotidine and orotic acid excretion after the administration of a 300-mg oral dose of allopurinol in 25 [corrected] women who were obligate heterozygotes, 13 who were probable heterozygotes, 15 mothers of affected boys from monoplex families (families with only one affected member), 12 mothers of affected girls from monoplex families, and 21 [corrected] normal, unrelated women who were not carriers. Urinary orotidine excretion was increased 3 SD or more above the mean value for the normal women in 95.8 percent of the obligate heterozygotes, 84.6 percent of the probable heterozygotes, 73.3 percent of the mothers of affected boys in monoplex families, and 33.3 percent of the mothers of affected girls in monoplex families, thus establishing that these women were carriers of a mutant ornithine carbamoyltransferase allele. The presence of allopurinol-induced orotic aciduria was not as sensitive or specific an indicator of carrier status as the presence of orotidinuria. We conclude that measurement of urinary orotidine excretion after the administration of allopurinol is a simple and reliable test for the identification of women who are heterozygous for ornithine carbamoyltransferase deficiency.

Adult↗

PubMed1988

Alpha-tocopherol is secreted from rat liver in very low density lipoproteins.

Three separate studies were carried out to test the hypothesis that rat liver secretes vitamin E (alpha-tocopherol) within very low density lipoproteins (VLDL). i) When the clearance of plasma chylomicrons (CM) and VLDL was blocked by the administration of Triton WR-1339, alpha-tocopherol concentrations increased linearly with time in both classes of triacylglycerol-rich lipoproteins, although accumulation rates within VLDL exceeded those within CM. For fasted rats, appearance of alpha-tocopherol in VLDL persisted at slightly reduced rates. alpha-Tocopherol and triglycerides in the VLDL fraction responded to Triton WR-1339 administration by coordinate increases. In contrast to the situation in serum, alpha-tocopherol concentrations decreased in the liver following injection of Triton. ii) In order to inhibit the secretion of hepatic lipoproteins containing apolipoprotein B (apoB), rats were fed a diet containing orotic acid. This resulted in a reduction of apoB and alpha-tocopherol concentrations in serum and VLDL, whereas the vitamin E content of liver was increased. iii) In primary cultures of hepatocytes, alpha-tocopherol was secreted into the culture media predominantly within VLDL. We, therefore, conclude that the liver secretes alpha-tocopherol within VLDL and in this way contributes to the maintenance of serum vitamin E concentrations.

Animals↗

PubMed1984

On some mechanisms of antihypoxic actions of nootropic drugs.

The antihypoxic effect of meclofenoxate hydrochloride seen in the accelerated restitution of posthypoxic dopamine release inhibition originates in the alcoholic component of the drug. Via choline dimethylaminoethanol might run, like orotic acid, into a CDP-choline pool, the generation of which is able to be facilitated by piracetam which in turn increases the phosphorylation potential. All these nootropic drugs will in this way increase the biosynthesis of hypoxically vulnerable phospholipids by different mechanisms. Indeed, a combined treatment with piracetam, meclofenoxate hydrochloride and methylglucamineorotate leads to a more rapid restitution of posthypoxic dopamine release inhibition than the drugs are active when applied separately.

Animals↗

PubMed1994

Normalization of hair growth in sparse fur-abnormal skin and hair (SPF-ASH) mice by introduction of the rat ornithine transcarbamylase (OTC) gene.

The sparse fur-abnormal skin and hair (SPF-ASH) mouse is a model for the human X-linked hereditary disease, ornithine transcarbamylase (OTC) deficiency. This condition is characterized by abnormal skin and delayed hair growth, hyperammonemia, orotic aciduria and low levels of serum citrulline and arginine. Murakami et al. [1] established a line of transgenic mice, by introducing the recombinant rat OTC (rOTC) gene into fertilized C57BL mouse eggs. We introduced the rOTC gene into SPF-ASH mice by mating SPF-ASH heterozygotes and transgenic mice, which carried this gene. The hemizygous SPF-ASH mice bearing the rOTC gene showed normal hair growth without sparse fur, normal urinary orotic acid excretion and normal serum citrulline and arginine levels. These mice showed OTC activities 2 and 6 times higher in the liver and small intestine, respectively, than the SPF-ASH mice but about 12% and 27% those of the controls [2].

Animals↗

PubMed1986

Effect of chlorpromazine on protein, phospholipid and RNA synthesis or degradation in rat liver.

Chlorpromazine (CPZ) administration to rats (25 mg/kg ip) significantly stimulated (14C)-leucine incorporation to liver microsomal proteins, (14C)-orotic acid incorporation to liver RNA and (32P) incorporation to liver microsomal lipids. CPZ administration did not modify the decay of radioactivity of liver microsomal lipids prelabeled with (32P) or that of microsomal proteins prelabeled with [(14C)-guanidino]-arginine. Results suggest that CPZ administration stimulates protein, phospholipids and RNA synthesis but does not affect their degradation. The relation of these findings with CPZ preventive effects on CCl4-induced liver injury is discussed.

Animals↗

PubMed1976

[Stimulation of RNA synthesis in rat liver and isolated hepatocytes by silybin, an antihepatotoxic agent from Silybum marianum L. Gaertn (author's transl)].

The incorporation of [3H] orotic acid into RNA from rat livers is stimulated by the flavonolignane derivative Silybin. The time course of the RNA synthesis and its dose dependence were demonstrated with isolated hepatocytes and [3H]uridine. The specific radioactivity of the newly synthesized RNA in rats treated with silybin is markedly higher than that of the controls. From preliminary experiments there is no indication that the synthesis of a distinct species of RNA is stimulated preferentially.

Animals↗

PubMed1999

Development of resistance during the early stages of experimental liver carcinogenesis.

The present study was designed to determine whether the resistant phenotype is acquired at the initiated cell stage itself or requires further exposure to a promoting regimen to express resistance. Male Fischer 344 rats were initiated with diethylnitrosamine (DENA) (200 mg/kg i.p.) and were subjected to either no further treatment or to the resistant hepatocyte (RH) model of liver tumor promotion. Six weeks later, the resistance of the focal lesions generated in these two groups to the mitoinhibitory effects of 2-acetylaminofluorene (2-AAF) was determined by subjecting the rats to two-thirds partial hepatectomy (PH) in the presence of a mitoinhibitory dose of 2-AAF (5 mg/kg i.p.) given at the time of PH. Labeling index was determined by administering multiple injections of [(3)H]thymidine. All rats were killed 48 h post-PH. While only a small percentage (23%) of the glutathione S-transferase-positive foci generated by DENA in the absence of an exogenous liver tumor promoting regimen were resistant to the mitoinhibitory effects of 2-AAF, a majority (85%) of the foci became resistant to 2-AAF following exposure to the RH model of liver tumor promotion. Further, initiated rats exposed to either 2-AAF or to CCl(4) alone, the two components of the RH model, resulted in 71% of the foci being resistant to the mitoinhibitory effects of 2-AAF. Similar patterns of results were obtained when the resistance of the foci to the mitoinhibitory effects of orotic acid, a liver tumor promoter and an inhibitor of DNA synthesis in normal hepatocytes, was monitored. These results suggest that the majority of initiated hepatocytes are not of resistant phenotype, however, they have acquired a unique ability to express resistance upon exposure to certain agents such as 2-AAF and CCl(4) or to a promoting regimen such as the RH model of liver tumor promotion.

2-Acetylaminofluorene↗

PubMed1987

Increase of protein synthesis by uridine supplement in lectin-stimulated peripheral blood lymphocytes and EB virus-transformed B cell line of hereditary orotic aciduria type I.

A 2 month-old Japanese girl with hereditary orotic aciduria type I was treated with oral uridine supplement. The activities of orotate phosphoribosyltransferase (OPRT) and orotidine-5'-phosphate decarboxylase (ODC) in erythrocytes were 2.7 and 0.4%, respectively, of those in the controls. Megaloblastic anemia, excessive urinary excretion of orotic acid, lymphopenia and decreased number of OKT3 positive lymphocytes on admission were corrected after the uridine supplement. Peripheral blood lymphocytes (PBL) were cultured for 24 hr in RPMI 1640 medium with 10% heat-inactivated fetal calf serum and further stimulated with PHA-P, ConA or PWM in the presence of 10 to 1000 microM uridine. EB virus-transformed B cell line (LCL) maintained with an optimal concentration of uridine was cultured for 48 hr in uridine free medium and cultured for an additional 48 hr with 1 to 1000 microM uridine. The incorporations of leucine in to PHA-, ConA- and PWM-stimulated PBL and into LCL of the patient increased in the presence of uridine over 10 microM, although they did not increase in controls. These data suggest that low protein synthesis might correlate with an immune deficiency in hereditary orotic aciduria type I.

Antigens, Surface↗

PubMed1978

Effect of insulin on RNA and protein biosynthesis in liver mitochondria from normal and alloxan diabetic rats.

In liver mitochondria from alloxan diabetic rats the biosynthesis of RNA (as measured by 14C-orotic acid incorporation and RNA polymerase activity) and protein (as measured by 14C-leucine incorporation) were decreased. In contrast, insulin (20 U kg-1) injected to intact or diabetic rats increased both these measures. However, no change of mitochondrial DNA biosynthesis (as measured by incorporation of 3H-thymidine) was found. It was concluded that in liver cells insulin plays an important role in regulation of biosynthesis not only of nuclear (cytoplasmic) but also of mitochondrial RNA and proteins.

Animals↗

PubMed1989

Biogenesis of plasma lipoproteins in rat hepatoma McA-RH7777: importance of diffusion-mediated events during cell growth.

Cultured McA-RH7777 rat hepatoma cells actively synthesize and secrete plasma lipoproteins. However, synthesis of [14C]triglyceride declines monotonically throughout the early growth period and remains low in postconfluent cultures; and net secretion of [14C]triglyceride is 10-fold more efficient in logarithmically growing cultures than in postconfluent cultures. Secretion of apolipoproteins associated with very low density and low density lipoproteins is selectively reduced in postconfluent cultures. The temporal reductions in [14C]triglyceride production are related more strongly to increasing cell concentration (cells/cm3 medium) than to increasing cell density (cells/cm2 growth surface). We have allowed cells to grow either retained within small circular corrals or unrestricted in culture dishes. When seeded at equal density (10(4) cells/cm2) but at one-fifth the cell concentration, corralled cells synthesize twice as much [14C]triglyceride per cell after 2 and 4 d, and are 10 times as efficient in [14C]triglyceride secretion by 6 d of growth, as noncorralled cells. When seeded at equal cell concentration (10(5) cells/dish) but at 5 times the cell density, corralled cells are only 20% less efficient at [14C]triglyceride synthesis and secretion than noncorralled cells. Conditioned medium depresses synthesis and secretion efficiency of [14C]triglyceride. Orotic acid exposure also inhibits synthesis of [14C]triglyceride and secretion of certain [35S]apolipoproteins in early cultures, but it has no significant effect on late cultures. We conclude that diffusion-mediated events are important regulators of triglyceride and apolipoprotein production in growing rat hepatoma cells, but that events associated with formation of cell-to-cell contacts play a minor role in regulation of plasma lipoprotein biogenesis.

Albumins↗

PubMed1966

Observations on the biosynthesis of thiamine in yeast.

1. Methods are described for the isolation of radioactively pure thiamine from yeast and its degradation on a small scale to its cyclic components. 2. A degradation of the pyrimidine ring and a thin-layer method for the separation of thiamine, its derivatives and pyrimidine and thiazole residues are described. 3. [(14)C]Formate is more effectively incorporated into the pyrimidine residue than into the thiazole residue, whereas the reverse is true with l-[Me-(14)C]methionine. 4. Experiments with [Me-(14)C,(35)S]methionine demonstrate that methionine provides an intact unit for the biosynthesis of the thiazole ring. 5. [6-(14)C]Orotic acid is insignificantly incorporated into the pyrimidine residue of thiamine. 6. Experiments with [1-(14)C]- and [2-(14)C]-acetate indicate that it is incorporated as a unit into the thiazole residue, but that only C-2 is incorporated into the pyrimidine residue. 7. l-[U-(14)C]Alanine is also effectively incorporated into the thiazole residue. 8. These results are discussed in relation to possible pathways of biosynthesis of the two ring components of the thiamine molecule.

Acetates↗

PubMed1985

Triiodothyronine-stimulated RNA synthesis in primary cultures of adult rat hepatocytes.

We have studied the effect of triiodothyronine (T3) on RNA synthesis by primary cultures of rat hepatocytes in order to ascertain whether hepatocyte transcriptional activity is directly stimulated by this hormone. The results demonstrate that T3 stimulates RNA synthesis as measured by [3H]orotic acid incorporation into RNA and by RNA polymerase activity. The responsiveness of cultured hepatocytes to T3 becomes evident only after a fairly long latency period required for the recovery of T3 nuclear binding sites. The response of RNA synthesis to T3 was absent unless the hepatocytes were simultaneously exposed to insulin and dexamethasone, indicating a permissive role of these factors in the action of T3 on RNA synthesis.

Animals↗

PubMed1976

Abnormal ornithine carbamoyltransferase in mice having the sparse-fur mutation.

Mice with the X-chromosomal sparse-fur (spf) mutation frequently have urinary bladder stones composed mostly of orotic acid, which was identified by the following criteria: ultraviolet and infrared absorption, spectra, chromatographic behavior, melting point, and reactivity in a specific color test. This clue led to the discovery that spf-bearing mice have an abnormal form of liver ornithine carbamoyltransferase (carbamoylphosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3). Normal ornithine carbamoyltransferase has maximum activity at pH 7.6-8.0 and 80% of maximum activity at pH 10.0.

Alleles↗

PubMedDate not supplied

[Turnover of nuclear RNA. III. Detection and characterization of superstable molecules].

In prolonged experiments in which rats were injected with 14C-orotic acid for 7-10 days with subsequent measurements (during 1-2 months) of the label in various rat liver RNA fractions and in the acid-soluble pool, a superstable nuclear RNA fraction was found (T1/2-4.2 days in quiescent rat liver and 4.3 days in regenerating rat liver). A small fraction of this RNA (5-10% of total) is polyadenylated and heterogeneously distributed when electrophoresed in 1% agarose under partially denaturing conditions. Using the conveyer model of synthesis and processing of nuclear RNA advanced earlier the spectrum of turnover rates of superstable transcripts was determined. The data obtained are discussed in light of the hypothesis on posttranscriptional regulation of gene expression.

Animals↗

PubMed1980

[Characteristics of synthesized RNA in the isolated and perfused rat liver].

The incorporation of 3H-orotic acid into nuclear and microsomal RNA from isolated perfused rat liver has been studied. The specific radioactivity of nuclear RNA indicates that the efficiency for RNA synthesis in the perfused liver is similar to that of the liver 'in vivo'. In contrast, the microsomal RNA specific radioactivity is well below that observed 'in vivo'. This may indicate a slower transport of the labelled RNA from the nucleus to the cytoplasm. Labelling pattern of total nuclear RNA, nuclear poly(A) containing RNA and microsomal RNA appear to be in line with these assumptions.

Animals↗

PubMed1998

Dihydroorotate (dhout) and orotate (orout) utilizer mutants in yeast: identification of the dhout mutation and allelism of the DHO and URE2 genes.

We induced by UV mutagenesis a series of yeast mutants that were able to utilize dihydroorotic (dhout) and orotic acid (orout) as precursors for pyrimidine biosynthesis. These recessive mutations defined three complementation groups named dhout, orout1 and orout2. The wild-type allele of the gene responsible for dihydroorotate utilization was cloned using the sensitivity of the dhout mutant to 5-fluoroorotate. The DHO gene was sequenced and found to be identical to the URE2 gene. The dhout mutation resulted from the introduction of a stop codon instead of a glutamine at position 59, which led to the production of a truncated Ure2p. Therefore, the URE2 and DHO genes are alleles in yeast.

Alleles↗