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PubMed1986

The effect of dietary protein on nitrogen and sulfur metabolism in portacaval-shunted rats.

The effect of varying the amount of protein in the diet on postoperative recovery, plasma ammonia, urinary orotic acid and metabolism of sulfur-containing amino acids was examined in rats with portacaval shunts (PCS). Food intake and weight gain were lower in both PCS and control rats fed a low (6%) casein diet unsupplemented with methionine compared with rats fed an adequate (18%) casein diet. PCS rats fed 60% casein ate slightly less and took longer to recover their preoperative body weight compared to 60% controls. Shunted rats were consistently hyperammonemic and orotic aciduric compared to controls. Increasing protein in the diet elevated plasma ammonia and urinary orotic acid in all rats to levels above those of the rats fed 18% casein, but the effect was greater in rats with PCS. After i.p. injection of L-[35S]methionine or L-[35S]cysteine, urinary 35S and [35S]sulfate excretion increased and [35S]taurine and total taurine excretion decreased in all rats fed 60% casein. These changes are consistent with our observation that hepatic activities of cysteine dioxygenase and cysteine sulfinate:alpha-ketoglutarate aminotransferase increased and that of cysteine sulfinate decarboxylase decreased in rats fed the high protein diet. The effect of dietary treatment on both urinary taurine excretion and decarboxylase activity was greater in PCS rats than in controls. Although PCS rats fed a high protein diet may have a decreased taurine-synthesizing capability compared to controls, their ability to oxidize a methionine or cysteine load to sulfate is not compromised by feeding either an 18 or 60% casein diet.

Amino Acids, Sulfur↗
PubMed1978

[A new family with mutation of the structural gene of human ornithine carbamoyltransferase].

Studies of a child with hyperammonemia have demonstrated a deficiency in OCTase. The kinetic properties of the enzyme were studied and it could be shown that we have to deal with a new mutation which is different from the ones previously known. It is a mutation of the structural gene. The detection of a heterozygote is possible when the urinary orotic acid excretion is studied after a loading meal (2g of proteines per kilo of weight). A child with hyperammonaemia due to ornithine transcarbamylase deficiency is described. A new structural gene mutation is probable because the kinetic properties of the enzyme are different to previously described variants. The heterozygote could be detected by the measurement of the excretion of orotic acid in the urine following a protein load of 2 g/Kg.

Amino Acid Metabolism, Inborn Errors↗
PubMed1978

Effects of long term ethanol ingestion on RNA metabolism by inner membranes of rat brain mitochondria.

Recent laboratory endeavors have been primarily concerned with determining the effects of chronic ethanol ingestion on cerebral RNA metabolism within the inner mitochondrial membrane (IMM). Toward this goal, a series of experiments were carried out by determining the RNA and protein synthetic activity of the organelle. Brain mitochondria actively incorporated [5-3H]orotic acid into RNA under in vivo conditions. In addition, data showed that a major portion of the radioactivity present in the cold TCA insoluble residue from labeled intact mitochondria could be recovered in the digitonin treated purified IMM fraction. Maximum incorporation of [5-3H]orotic acid into RNA took place within 24 hrs followed by a rapid decline in activity on the 5th day of the pulse in both 'control' and 'ethanol' ingesting rats. Data revealed that ethanol ingestion affected the degree of incorporation of labeled RNA precursor into the mitochondrial RNA fraction. The observed effect was in the form of inhibition and was dependent on the duration of the initial pulse. Thus, while at earlier time points a decreased incorporation of the precursor into mitochondrial RNA was obtained in the ethanol imbibing rats, the inhibition was not observed when the pulse time was extended to 5 days. Such results indicate the possibility of a rapid turnover rate for the brain mitochondrial RNA with the 'ethanol' group having a faster rate of turnover when compared to the 'control' group.

Alcoholism↗
PubMed1985

Carbamoyl-phosphate synthetase I activity and ureagenesis in regenerating liver of the normal rat.

Urea excretion per gram of liver was increased 219% 2-5 h post-partial hepatectomy (Hx) and 45% 24-27 h post-Hx. Mitochondrial carbamoyl-phosphate synthetase was also increased 5 h post-Hx but was not increased at 27 h. An NH4+ load did not increase urea excretion per gram liver or the enzyme activity noticeably in the 2- to 5-h period but did increase them 24-27 h post-Hx. These results suggest that the enzyme activity and urea formation per unit weight of liver were nearly maximal early during regeneration. Orotic acid excretion per gram of liver in rats that received NH4+ was increased more than 30-fold 2-5 h post-Hx and was similar in this respect to nonhepatectomized rats. Ornithine prevented the increase in both normal and hepatectomized rats, suggesting that ornithine was rate limiting for the ornithine carbamoyltransferase (OCT) reaction. The orotic acid excretion response to NH4+ was much less 24-27 h post-Hx, indicating that ornithine availability for the OCT reaction may be increased at this time.

Ammonia↗
PubMed1984

The effect of purine and pyrimidine bases on splenic plaque-forming cells and cellular immunity.

The effects of a variety of purine and pyrimidine bases on splenic plaque-forming cells and cellular immunity in mice are presented. The antibody-forming plaque cells were measured in spleens of female C57/B1 mice by the Jerne plaque method using sheep red blood cells as the antigen. Bases were given on days 0 and 1 at doses varying from 2 to 200 mumoles per mouse and the antigen was given on day 0; the antibody response was measured on day 4. Cell-mediated immunity was measured by the survival of 1 cm2 skin allografts transplanted across an H-2 histocompatibility barrier in female mice from C57/B1 donors to Balb/c recipients. For the plaque assay, adenine given at 25 and 50 mumoles/mouse and adenosine at 100 mumoles/mouse, resulted in significant 7 to 14-fold immunosuppression. Adenosine at 25 and 50 mumoles/mouse and guanosine and hypoxanthine at 100 mumoles/mouse resulted in an approximate 2-fold immunoenhancement. 2'-Deoxyadenosine, inosine, guanine, 2'-deoxyguanosine and the pyrimidines cytosine, cytidine, 2'-deoxycytidine, 2'-deoxythymidine and uridine all given at 100 mumoles/mouse and orotic acid given at 25 mumoles/mouse had no significant effects on the plaque response; orotic acid at a dose of 50 mumoles/mouse was lethally toxic to mice. In the primary immune response adenine was immunosuppressive at day 4, but significantly immunoenhancing at days 7 and 11. In the secondary response, adenine was immunosuppressive up to day 3 of the IgG and IgM responses; however, immunoenhancement occurred at day 4 (IgM) and day 5 (IgG). In the cell-mediated immune response, adenine at doses of 25 and 50 mumoles/mouse resulted in a significant 40% increase in the survival of skin allografts across an H-2 histocompatibility barrier.

Animals↗
PubMed1982

Ammonia metabolism in dogs with portacaval shunts.

Plasma ammonia, arginine, citrulline and urine ammonia, total nitrogen, and orotic acid were measured in shunted and control dogs. The progressive rise in plasma ammonia in the experimental group could not be explained solely by shunt hemodynamics. Similarity of control and experimental urinary nitrogen does not implicate nitrogen load. Urea synthesis was similar in experimental and control liver slices and was augmented by ornithine only in the experimental slices. Additionally, elevated urine orotic acid suggests urea cycle compromise at the ornithine transcarbamylase step.

Ammonia↗
PubMed1987

Inhibitory effect of intravenous lysine infusion on urea cycle metabolism.

Intravenous infusion of 0.5 mmol/kg L-lysine monohydrochloride was performed in six normal volunteer subjects aged 10-14 years to study the inhibitory effect of lysine on urea cycle metabolism. The lysine infusion resulted in a significant increase in plasma levels of arginine and ornithine, and in urinary homocitrulline, putrescine, and orotic acid, accompanied by a significant increase in blood ammonia. There was little change in plasma urea and citrulline. The increase in plasma arginine appears to reflect an inhibited arginase activity although the plasma urea level did not change. The increased homocitrulline excretion suggests that ornithine conversion to citrulline via ornithine transcarbamylase (OTC) was inhibited. The simultaneous increase in plasma ornithine and urinary putrescine may reflect an inhibition of mitochondrial ornithine transport. In addition to the direct ammoniagenic property of lysine, impaired ornithine conversion to citrulline resulting from the inhibition of both OTC activity and mitochondrial ornithine uptake by lysine may be responsible for the increase in blood ammonia and urinary orotic acid. Despite the retarded citrulline formation, a promoted efflux of citrulline from mitochondria may have kept the plasma citrulline level unchanged.

Adolescent↗
PubMed1976

The action of cordycepin on nascent nuclear RNA and poly(A) synthesis in regenerating liver.

Following a 5 min pulse of [5- 3H]orotic acid via the protal vein, the specific radioactivity of non-poly(A)heterogeneous nuclear RNA (HnRNA) reaches a peak at 12 h after partial hepatectomy. In contrast, poly(A)-HnRNA was maximally elevated only at 2 h after operation. After intraportal injection of cordycepin (3'-deoxyadenosine) 1 min before [5-3H]orotic acid, a dose-dependent inhibition of nuclear HnRNA and rRNA occurred. Fractionation of HnRNA on poly(U)-Sepharose following 20 mg/kg of cordycepin revealed that a 65% reduction occurred in the labeling of poly(A)-HnRNA while non-polyactivity of UTP in control and cordycepin-treated animals indicated no significant alterations in these parameters. Assessment of poly(A) size using poly(A)-HnRNA annealed with oligo(dT)10 as template primer for Escherichia coli DNA polymerase I, showed that 20 mg/kg of cordycepin inhibited nuclear polyadenylylation by 43%; no alteration in the binding of poly(A)-HnRNA to Millipore filters occurred at this dose of cordycepin. These results indicate that cordycepin is a non-selective inhibitor of nuclear RNA and poly(A)synthesis in regenerating rat liver.

Animals↗
PubMed1981

Hydra viridis: transfer of metabolites between Hydra and symbiotic algae.

"Back transfer" of metabolites from food to endosymbiotic algae in the digestive cells of Hydra viridis was demonstrated. Brine shrimp nauplii labeled with tritiated precursors of protein and nucleic acids (DNA and RNA) were fed to light and dark grown hydras. The fate of the label after a single feeding with radioactive material in hydra and algal fractions was followed by scintillation counting and autoradiographic techniques. Labeled thymidine was incorporated into DNA in both light- and dark-grown hydras. Although the symbiosis persists indefinitely in hydras in darkness (7-10 days) the number of algae per cell is reduced. Tritiated orotic acid and tritiated uridine, RNA precursors, were incorporated into peptides and proteins, and to a lesser extent into simple sugars, oligosaccharides, and oligonucleotides in hydra and algal fractions. Thus the metabolites of the brine shrimp food are available to both partners. A decrease over time in label introduced as 3H-orotic acid and 3H-uridine and incorporated into hydra RNA is compensated for by an increase in label in the algae, implying competition for constant quantities of metabolites from the single feeding. Although food availability, light, number of algae per cell, and other factors influence the quantity and rate of nutrient transfer between the partners, in both light and dark grown hydras the amount of "back transfer" of metabolites to the symbiotic algae is impressive.

Animals↗
PubMed1975

Alterations in the metabolism of hamster tracheas in organ culture after infection by virulent Mycoplasma pneumoniae.

Exposure of hamster tracheal rings in organ culture to virulent Mycoplasma pneumoniae organisms leads to alterations in macromolecular biosynthesis and metabolic activity of the respiratory epithelial cells. Avirulent organisms derived from the same parent strain do not produce these effects. During the course of infection by virulent mycoplasmas, tracheal rings show an initial increase in [14C]galactose uptake followed by a significant decline as infection progresses which is also accompanied by abnormal processing of galactose as evidenced by amounts of 14CO2 released. Parallel decreases in the rate of [3H]orotic acid and [3H]amino acid uptake are observed. Within 24 h after infection of tracheal rings by virulent mycoplasmas, inhibition of host cell ribonucleic acid and protien synthesis is evident. Ribonucleic acid synthesis in infected cells, analyzed by gel electrophoresis, is reduced by 80% at 48 h and is negligible by 96 h. The course of mycoplasma infection can be interrupted or reversed by erythromycin after the initial mycoplasma-host cell interaction since addition of erythromycin 24 h or earlier after infection prevents the onset of abnormal orotic acid uptake. However, 48 h after infection, rescue of host cells by erythromycin cannot occur and cytopathology becomes evident. These data suggest that mediation of host cell injury requires continued protein synthesis by attached mycoplasmas, and the primary effect of mycoplasma infection on tracheal organ culture may be at a transcriptional or translational level.

Animals↗
PubMedDate not supplied

[Two pathways of pyrimidine nucleotide biosynthesis in birds].

Dillerent chicken tissues are shown to display a clearly pronounced specificity relative to [2-14C] orotic acid and [5-3H]uridine as precursors of synthesis of the pool and RNA pyrimidine nucleotides. The fraction of pyrimidine nucleotides synthetized relative to the reserve pathway (uridine utilization) decreases in the series: kidneys greater than duodenum mucosa greater than lungs greater than liver greater than pancreas greater than bone marrow greater than brain greater than spleen. The results of [2-14C]orotic acid and [53H]uridine incorporation into UMP and CMP of the liver and spleen tissues RNA are interpreted in terms of the concept on existence of separate pools of pyrimidine phosphates--RNA precursors.

Animals↗
PubMed1981

Orotic aciduria in lysinuric protein intolerance: dependence on the urea cycle intermediates.

Urinary excretion of orotic acid was measured in controls and in subjects homozygous and heterozygous for lysinuric protein intolerance under various conditions of amino nitrogen intake. In all situations, the controls excreted less than 28 microgram/kg/hr. Only one of the two heterozygotes studied differed from the controls, The orotic aciduria of homozygotes was normal in fasting but increased on a self-chosen low-protein diet (log mean, 80; range, 8 to 588 microgram/kg/hr in 24-hr urine), after cow's milk protein 0.5 g/kg (769; 251 to 1747 microgram/kg/hr in 4 to 6-hr urine), oral ammonium lactate, 2.5 mmoles/kg (95; 15 to 1127 microgram/kg/hr in 1.5-hr urine), and IV alanine, 6.6 mmoles/kg (519; 47 to 1831 microgram/kg/hr in 6-hr urine). Giving ornithine or citrulline IV with the infusion of alanine prevented the increase in orotic acid excretion. Given orally, citrulline was more efficient than ornithine or arginine. To prevent the hyperammonemic and orotic aciduric responses with ornithine its plasma concentrations needed to be higher than normal. Orotic aciduria is a reliable indicator of the function of the urea cycle in lysinuric protein intolerance and facilitates monitoring of the treatment of this disease.

Adolescent↗
PubMed1983

RNA synthesis in primary cultures of adult rat hepatocytes.

The ability of hepatocyte monolayers to synthesize RNA was investigated by measuring [3H]orotic acid incorporation into RNA and the total nuclear RNA polymerase activity as a function of the time in culture. The results demonstrate that primary cultures of hepatocytes maintained in a chemically defined serum- and hormone-free medium are able to synthesize RNA actively. This ability increases within the first 2 d of culture, despite the concomitant decrease in [3H]orotic acid uptake, and decreases only after 3 d. Factors such as serum, insulin, and dexamethasone, known to improve maintenance of functional hepatocytes, markedly stimulate the uptake of labeled precursor without apparently affecting the rate of RNA synthesis by cultured cells. It is suggested that the culture of adult rat hepatocytes provides a useful experimental model for the studies of hormonal regulation of transcription in liver.

Animals↗
PubMed1971

The stability of rat liver ribonucleic acid in vivo after methylation with methyl methanesulphonate or dimethylnitrosamine.

1. RNA was isolated from rat liver at selected times after the intraperitoneal injection of either [(14)C]methyl methanesulphonate (50mg/kg) or [(14)C]dimethylnitrosamine (2mg/kg). These doses were chosen to minimize effects due to toxicity. 2. Two methods of extraction and purification of RNA were used and an analysis of the radioactivity present was made by column chromatography of acid hydrolysates of the purified RNA. 3. The extent of methylation of guanine, the principal site of alkylation in rat liver RNA, was determined at times up to 14 days after injection. Although dimethylnitrosamine is a potent liver carcinogen and methyl methanesulphonate is not carcinogenic to rat liver, the rate of disappearance of 7-methylguanine from RNA was similar for both compounds, with a half-life of about 3.5 days. 4. An estimate of the biological half-life of rRNA was made by using [(3)H]orotic acid. A half-life of 5 days was obtained and this was not affected by injecting animals with unlabelled methyl methanesulphonate at the same dosage of 50mg/kg used in the studies of RNA methylation. 5. After administration of labelled orotic acid, reutilization of labelled RNA degradation products probably results in an overestimation of the biological half-life for rRNA. It is suggested that non-toxic doses of methylating agents such as methyl methanesulphonate and dimethylnitrosamine may prove to be a more effective way of accurately estimating the biological turnover of RNA species.

Alkanes↗
PubMed1985

Metabolism of uridine and determination of liver ribonucleic acid synthesis in developing and adult mice.

The metabolism of [5-3H]uridine and the incorporation of the precursor into liver RNA was studied in developing (13-day-old) and adult (45-day-old) mice. Different time-courses of labelling and increased amounts of labelled catabolic products of uridine were found in liver and blood of developing mice compared with adult animals. This is suggested to be a consequence of enlarged metabolite pools resulting from a lower total amount of uracil-degrading enzymes in the developing mice. The labelling of the uracil nucleotides was decreased in the developing liver. However, in spite of a lower specific radioactivity of UTP, the RNA-specific radioactivity of developing liver was increased compared with adult liver. Also the labelling of liver RNA with [6-14C]orotic acid was found to be increased in developing mice, thus indicating a higher rate of RNA synthesis in these animals. A more pronounced difference in liver RNA labelling between the developing and the adult mice obtained with the use of [14C]orotic acid than with [3H]uridine may suggest that the de novo pathway, relative to the salvage pathways, is more important in developing than in adult liver.

Aging↗
PubMed1977

Effects of protein deficiency on the biosynthesis and degradation of ribosomal RNA in rat liver.

Employing livers from rats fed on a protein-free diet for two weeks, the effects of protein deficiency on both biosynthesis and degradation of rRNA were investigated and the following results were obtained. 1. Protein deficiency led to a decrease of total liver RNA content per DNA to about 80% of that in normal rat liver. 2. From the kinetics of rRNA labelling with [14C]orotic acid in vivo, the half-lives of cytoplasmic rRNA's of normal and protein-deficient rat livers were determined to be 6.2 and 5.1 days, respectively. Furthermore, considering the pool size of rRNA in rat liver, the turnover rate of cytoplasmic rRNA was calculated to be 0.212 pmole/min/mg of nuclear DNA in normal rats and 0.240 pmole/min/mg of nuclear DNA in protein-deficient rats. 3. From the electrophoretic patterns of nucleolar RNA's of both groups of rat livers labeled with [14C]orotic acid, the time courses of the specific activities of nucleolar 45S, 32S, and 28S rRNA's were analysed and the half-life of each nucleolar RNA in both groups of rat livers was determined. Nucleolar 45S, 32S, and 28S RNA's had half-lives of 6.0, 15.9, and 26.5 min in normal rats, respectively, and 5.5, 19.4, and 22.9 min in protein-deficient rats, respectively Considering the pool size of each nucleolar RNA obtained from the leectrophoretic pattern, the turnover rates of 45S, 32S, and 28S RNA's were calculated to be the same, i.e., o.189 pmoles/min/mg of nuclear DNA, in normal rat liver and 0.372, 0.372, and 0.358 pmoles/min/mg of nuclear DNA in protein-deficient rat liver, respectively. 4. These results indicate that protein deficiency increased both the rate of degradation of cytoplasmic rRNA and that of nucleolar rRNA synthesis in rat liver. While in normal rat liver the rates of rRNA synthesis and degradation were rather similar, the rate of rRNA synthesis in protein-deficient rats was about 1.5 times higher than that of its degradation. Therefore, the decrease of total liver RNA content in protein deficiency might be accounted for by stimulated degradation of rRNA in the nucleus. 5. The activities of RNase in nuclear fractions of both groups of rat livers were compared. Both activities of nuclear acid RNase and especially that of the free form of alkaline RNase in protein-deficient rat liver were higher than those in normal rat liver.

Animals↗
PubMed2000

Effect of lysine infusion on urea cycle in lysinuric protein intolerance.

Poor intestinal absorption and excessive renal loss of dibasic amino acids result in low plasma concentrations in patients with lysinuric protein intolerance (LPI). Arginine and ornithine deficiency impair the function of the urea cycle and cause hyperammonemia after protein intake, while chronic lysine deficiency may cause growth failure and lead to reduced bone density in such patients. Since high lysine concentrations inhibit several enzymes of the urea cycle in the liver, lysine supplementation may induce hyperammonemia in LPI. We thus studied how LPI patients tolerate high plasma lysine by intravenous (IV) infusion of 3.3 mmol/kg lysine hydrochloride over 90 minutes in 6 adult patients and 4 healthy controls. The plasma lysine concentration (mean +/- SD, range) peaked in the patients (9,114 +/- 1,864, 7,156 to 12,044 micromol/L) and controls (10,185 +/- 2,253, 7,714to 13,122 micromol/L) at 90 minutes. Urinary lysine excretion peaked in the second 2-hour urine collection in the patients (4,582 +/- 1,276, 3,018 to 6,315 micromol/m2 body surface area per hour) and in the first 2-hour collection in the controls (5,373 +/- 1,766, 3,551 to 7,286 micromol/m2/h). Two patients had mild nausea but no hyperammonemia and one patient had moderate hyperammonemia (peak, 112 micromol/L) at the end of the infusion. Orotic acid excretion increased in 2 subjects with a peak excretion rate of 33 and 251 micromol/m2/h in the third 2-hour collection after starting the load. All other subjects remained asymptomatic and showed no change in plasma ammonia or urinary orotic acid excretion. We thus conclude that an acute increase in plasma lysine caused minimal clinical or biochemical untoward effects in patients with LPI. Moderate increases in plasma lysine after low-dose oral supplementation with lysine or well-absorbed lysine derivatives are probably well tolerated in LPI.

Adult↗
PubMedDate not supplied

Intestinal fat malabsorption in the uremic rat.

In the past we have shown that patients with chronic renal failure (CRF) on hemodialysis show evidence of intestinal malabsorption of fat. The present study was designed to verify this finding in an animal model. Male rats weighing +/- 200 g were studied. Uremia (U) was induced by 2-stage subtotal (5/6) nephrectomy. Control (C) animals were sham-operated. Fat absorption was studied after 6 weeks of uremia with the oral fat loading test. Twenty percent intralipid (0.25 g/100 gBW) was given by gastric tube feeding to fasting animals and the appearance of chylomicrons (CHYL) and the rise of triglycerides (TG) in the serum was followed for 5 hrs. In order to isolate the effect of fat absorption, an additional group of U and C animals was pretreated with orotic acid and triton, thus blocking hepatic TG synthesis and neutralizing peripheral lipoprotein lipase activity. The absorption of CHYL was significantly (p less than 0.01) impaired in all U animals and averaged 43 and 70 percent of that of the C animals, 1 and 2 hrs after the load respectively. The rise in serum TG did not differ from C in mildly U animals (Scr 1.0 +/- 0.04). In the more severely uremic animals (Scr 2.6 +/- 0.2), however, pretreated with orotic acid and triton, the rise in serum TG was far less (p less than 0.01) than in C animals (111 +/- 26-903 +/- 111 delta % V.780 +/- 170-5032 +/- 746 delta %) 1 and 5 hrs after the load.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗