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At least 235 records · Page 13Linked to original sources
PubMed1989

The impaired tolerance of the recently infarcted rat heart to cardioplegic arrest: the protective effect of orotic acid.

After myocardial infarction, a reduced mass of non-infarcted myocardium remains to maintain cardiac output. This acutely stressed, non-infarcted myocardium exhibits many metabolic disturbances, and undergoes a process of acute hypertrophy. These stress-induced disturbances may reduce the tolerance of the heart to the global ischaemia of cardioplegic arrest and may explain the increased mortality and morbidity associated with cardiac surgery in patients with recent myocardial infarction. We postulated that orotic acid, a pyrimidine precursor which augments the rate of protein synthesis during hypertrophy, might improve the response of the recently infarcted heart to cardioplegic arrest. Myocardial infarction was induced in rats by coronary ligation, and after 2 days or 3 days the hearts were excised and perfused on the working heart apparatus. After measurement of work capacity, the hearts underwent 1 hour of hypothermic cardioplegic arrest. Post-arrest function was then measured and expressed as a percentage of the pre-arrest value. A group of sham-operated, non-infarcted hearts served as controls. There were two distinct findings: (1) when subjected to hypothermic cardioplegic arrest 2 days after myocardial infarction, hearts recovered only 49% of pre-arrest function, compared with 80% recovery in non-infarcted controls (P less than 0.001). Three days after infarction, recovery had improved to 68% (P less than 0.01 vs. 2 days, P less than 0.05 vs. non-infarcted). (2) Treatment with oral orotic acid following infarction augmented recovery from cardioplegic arrest to 83%, 2 days after infarction (P less than 0.001 vs. untreated) and to 87%, 3 days after infarction (P less than 0.01 vs. untreated).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Expression of N-acetylglucosaminyltransferase III in hepatic nodules during rat liver carcinogenesis promoted by orotic acid.

The activity of N-acetylglucosaminyltransferase III, which adds a "bisecting" GlcNAc in beta 1,4 linkage to the beta-linked Man of the core of Asn-linked oligosaccharides (Narasimhan, S. (1982) J. Biol. Chem. 257, 10235-10242), was determined in hepatic nodules of rats initiated by administration of a single dose of carcinogen 1,2-dimethylhydrazine.2HCl (100 mg/kg, intraperitoneal) 18 h after partial hepatectomy and promoted by feeding a diet supplemented with 1% orotic acid for 32-40 weeks. N-Acetylglucosaminyltransferase III was assayed using glycopeptide GlcNAc beta 1,2Man alpha 1,6(GlcNAc beta 1,2Man alpha 1,3)Man beta 1, 4GlcNAc beta 1,4GlcNAc-Asn as substrate and, as enzyme sources, microsomal membranes of the hepatic nodules, surrounding liver, regenerating liver, and age- and sex-matched control liver. The nodules had significant N-acetylglucosaminyltransferase III activity (0.78-2.18 nmol GlcNAc transferred/h/mg of protein), while the surrounding liver, the regenerating liver (24 h after partial hepatectomy), and the control liver had negligible activity (0.02-0.03 nmol/h/mg of protein). Product isolated from a large scale N-acetylglucosaminyltransferase III incubation with hepatic nodules as enzyme source showed the presence of the bisecting GlcNAc residue by 500 MHz proton NMR spectroscopy. Concomitant with the appearance of N-acetylglucosaminyltransferase III activity in the preneoplastic nodules, the activities of N-acetylglucosaminyltransferase I and II were decreased in these membranes when compared to those from surrounding liver, regenerating liver, and control liver. These results suggest that N-acetylglucosaminyltransferase III is induced at the preneoplastic stage in liver carcinogenesis promoted by orotic acid and are consistent with the reported presence of bisecting GlcNAc residues in the Asn-linked oligosaccharides of rat and human hepatoma gamma-glutamyl transpeptidase and their absence in enzyme from normal liver of rats and humans (Kobata, A., and Yamashita, K. (1984) Pure Appl. Chem. 56, 821-832).

1,2-Dimethylhydrazine↗
PubMed1983

Memory retention in old rats: improvement by orotic acid.

The effect of methylglucamine orotate (MGO) on learning and memory was investigated in 24-month-old rats using brightness discrimination in a Y-chamber and active avoidance in a shuttle box. In both learning procedures, an improvement of memory retention following 5-day MGO treatment (225 mg/kg per day) was observed. The retention of untreated old animals was significantly lower compared to 8-week-old rats. MGO treatment resulted in a significant improvement of retention in old rats, which nearly compensated for their memory deficit.

Aging↗
PubMed1980

Facilitated transport of uracil and 5-fluorouracil, and permeation of orotic acid into cultured mammalian cells.

The mode of permeation of uracil, 5-fluorouracil, and orotic acid into cells has been investigated in four established cell lines (Novikoff rat hepatopma, P388 mouse leukemia, mouse L., and Chinese hamster ovary cells) in attempts to assess the rate-determining step(s) in their incorporation into the nucleotide pool and nucleic acids. Uracil and 5-fluorouracil shared a saturable transport system (Km = 5 to 15 mM) capable of rapid equilibration of these substrates across the cell membrane (t 1/2 at 25 degrees in first-order range of concentration = 25 to 58 sec). Thus it seems unlikely that transport is limiting the incorporation of uracil or fluorouracil. Their transport was inhibited by various nucleosides and hypoxanthine. Only the non-ionized form of fluorouracil was a substrate for the transporter; exclusion of charged pyrimidines may explain why orotate was not a substrate at physiological pH. Orotate permeated the cell membrane much more slowly (t 1/2 = 2890 to 6930 sec); its permeation was apparently non-mediated and rate-determining in the conversion of extracellular orotate to intracellular nucleotides.

Animals↗
PubMedDate not supplied

Orotic acid in clinical urine specimens by capillary zone electrophoresis using polyvinyl alcohol coated capillaries.

Orotic acid is an important compound in the investigation of several inherited metabolic diseases, and capillary zone electrophoresis provides an effective assay method for this analyte in the clinical laboratory setting. Capillaries with a polyvinyl alcohol (PVA) coating performed well in this application. However, it was necessary to employ several specimen preparation steps to achieve good assay precision.

Electrophoresis, Capillary↗
PubMed1991

Relationship between DNA topoisomerase I activity and DNA synthesis in cultured hepatocytes: effects of orotic acid.

Previous studies have demonstrated that DNA topoisomerase I activity can be closely related to DNA replication and active transcription in different experimental models. This relationship was further investigated by studying the time course of DNA topoisomerase I activity in cultured rat hepatocytes stimulated by epidermal growth factor. This mitogen has been shown to stimulate DNA synthesis in liver cells both in vivo and in vitro. DNA topoisomerase I activity was assayed quantifying ATP-independent relaxation of a negatively supercoiled plasmid, substrate for the enzyme. Incubation of cellular extracts was carried out at 30 degrees C for 15'. Products were electrophoresed and analyzed by densitometry. DNA synthesis was measured as [3H]thymidine incorporation in the hepatocytes, after a 2 hrs pulse labelling. An increase in DNA topoisomerase I activity was observed early after epidermal growth factor addition, before the onset of DNA synthesis. Concomitant administration of orotic acid, which has recently shown mitoinhibitory effect, abolished the EGF-induced activity as well as DNA synthesis. Taken together these data indicate that, in cultured hepatocytes, the induction of DNA synthesis is supported by DNA topoisomerase I with a precise time schedule. Orotic acid administration abolishes this response and causes an overall loss in DNA topoisomerase I activity.

Animals↗
PubMed1997

Decreased secretion of very-low-density lipoprotein triacylglycerol and apolipoprotein B is associated with decreased intracellular triacylglycerol lipolysis in hepatocytes derived from rats fed orotic acid or n-3 fatty acids.

Hepatocytes from rats fed a chow (control) diet or from rats fed a chow diet supplemented with either orotic acid (OA; 1%, w/w) or fish oil (FO; 20%, v/w) were maintained in culture for periods up to 48 h. during the first 24 h period, the low rates of output of very-low-density lipoprotein (VLDL)-associated triacylglycerol (TAG) and apolipoprotein B (apoB) in hepatocytes from the FO- and OA-fed animals were associated with significantly lower rates of intracellular TAG lipolysis and re-esterification. Most of the VLDL TAG secreted was mobilized via lipolysis of the intracellular TAG pool, but the proportion of VLDL TAG secreted via this route in cells from the FO-fed and OA-fed animals was decreased compared with that in the control-fed animals' cells. In the presence of exogenous oleate the inhibitory effect of OA feeding on VLDL apoB and TAG secretion persisted in the derived hepatocytes for up to 48 h following isolation. However, when oleate was absent no inhibitory effect on the secretion of TAG and apoB was observed between 24 and 48 h. Under these conditions the rate of intracellular TAG turnover returned to normal. The initial inhibitory effect of FO feeding on VLDL TAG and apoB secretion did not persist in the derived hepatocytes between 24 h and 48 h of culture in the presence of exogenous oleate. Although intracellular TAG lipolysis and VLDL TAG and apoB secretion rates appear to be positively correlated, a causal relationship has not been conclusively established.

Animals↗
PubMed1981

Effect of some dietary additions to either an arginine-devoid diet or a diet supplemented with orotic acid refed after starvation on liver lipid content during essential fatty acid deficiency in rats.

Refeeding either an arginine-devoid diet or a 14% casein diet supplemented with 1% orotic acid for 7 days to starved rats caused an increase in liver lipid content which was prevented by the addition of adenine, allopurinol and safflower oil, but not guanine, cytosine, thymine and uracil. When rats were refed the arginine-devoid diet unsupplemented or supplemented with guanine, cytosine, thymine and uracil, their serum triglyceride and cholesterol decreased or tended to decrease as compared with those of rats refed the arginine-devoid diet supplemented with either adenine or allopurinol or rats refed the arginine-supplemented diet. Furthermore, triglyceride and cholesterol in serum of rats refed the arginine-devoid diet supplemented with either adenine or allopurinol increased as compared with those of rats refed the arginine-supplemented diet. The addition of either adenine or allopurinol to the arginine-devoid diet resulted in lowered lipid content in the liver as compared with the arginine-supplemented diet. Thus, when the arginine-devoid diet unsupplemented or supplemented with arginine, adenine and allopurinol was refed, liver lipid content was inversely related to the serum triglyceride level.

Adenine↗
PubMedDate not supplied

[Isolation of orotic acid from the liver and its metabolism in the rat].

A method is described for isolation of orotic acid from rat liver tissue for study of the kinetics of its radioisotopic labelling. Within 24 hrs after injection of 400 mg hydroxylamine per kg of body mass, the concentration of hepatic orotate decreased, while its transport into liver tissue and the kinetics of labelling of its endogenous pool remained unaffected.

Animals↗
PubMedDate not supplied

Dietary orotic acid, a new selective growth stimulus for carcinogen altered hepatocytes in rat.

It was observed that orotic acid (OA), a precursor for pyrimidine nucleotide biosynthesis, when supplied exogenously at 1% level in the diet selectively stimulated the growth of hepatocytes modified by 1,2-dimethylhydrazine (1,2-DMH) to form gamma-glutamyltransferase (gamma-GT) (EC 2.3.2.2) positive islands. Increasing the duration of OA diet from 5 to 10 weeks resulted in an increase in the number of foci from 6 to 14/cm2. Rats that received the carcinogen and basal diet, however, developed only 1-2 foci/cm2. This unique effect of OA can be further accentuated by supplying a liver cell proliferative stimulus, such as a single necrogenic dose of CCl4.

Animal Feed↗
PubMed1991

Effect of orotic acid on the generation of reactive oxygen and on lipid peroxidation in rat liver.

The pyrimidine precursor orotic acid (OA) is a constituent of dairy products and therapeutic drugs. Several recent publications point towards a tumor promoting activity of OA in rat liver. An increased production of reactive oxygen has been discussed as a possible mechanism, leading to lipid peroxidation and DNA single strand breaks. In view of contradictory results, this postulated prooxidative action of OA was reexamined with new experimental techniques. Weanling Sprague-Dawley rats were fed 1% OA in different diets for 4-35 days. The NADPH-mediated lipid peroxidation in liver homogenate and microsomes was determined in vitro by analysis of low-level chemiluminescence (CL) and the strongly correlated formation of malondialdehyde (MDA). In no case did treatment with OA result in an increase of lipid peroxidation in vitro nor did such treatment enhance the generation of reactive oxygen as measured by lucigenin CL. In accordance, the total cytochrome P-450 content as well as the activity of individual P-450 isoenzymes were unchanged. Treatment with OA did not elevate the MDA content of fresh liver homogenate when butylated hydroxytoluene (BHT) was present in the test system. However, when the antioxidant was omitted, increased levels of thiobarbituric acid reactive material were found which correlated with the triglyceride content. This could explain some published data that have been taken as indication for a prooxidative action of OA. Evidence against an increased lipid peroxidation in vivo is given by the analysis of ethane exhalation. Furthermore, no increase in DNA single strand breaks by OA treatment could be observed by the alkaline elution technique. These results do not support the hypothesis of a prooxidative activity of OA. The observed reversible decrease of the GSH/GSSG ratio is assumed to result from the reduced size of the phosphopyridine nucleotide pool due to purine deficiency and an increased consumption of NADPH by the enhanced reductive degradation of pyrimidines.

Administration, Oral↗