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PubMedDate not supplied

The increase of phospholipase C activity induced by orotic acid is unrelated to lipid peroxidation.

Liver phospholipase-C (PL-C) activity proved to be promptly modified in rats fed with an orotic acid (OA) supplemented diet; an increased of PL-C basal activity was demonstrated after 2 days of diet. In the present work the possible involvement of lipid peroxidation was investigated, since 4-hydroxynonenal (HNE) and 4-hydroxyoctenal (HOE), two end-products of lipid peroxidation, have been shown to induce a strong stimulation of hepatic PL-C. Membrane-bound PL-C activity was evaluated together with the rate of TBArs production by liver homogenates obtained from rats fed with a diet containing 1% OA for 2 and 5 days. PL-C activity was measured by following the rate of formation of Ins-P3 from labelled PtdIns-P2 added to isolated liver membranes. TBArs production was unchanged in the livers of rats fed the OA diet, while basal and GTPgammaS-stimulated PL-C activity increased; furthermore PL-C stimulation by bombesin was deeply impaired by OA.

Animals↗
PubMed1993

The development of hepatocellular carcinoma in initiated rat liver after a brief exposure to orotic acid coupled with partial hepatectomy.

Previous work from this laboratory has revealed that a minimum of 10-20 weeks of continuous exposure to 1% dietary orotic acid (OA) is necessary for this regimen to exert a significant promoting effect on the carcinogenic process in rat liver. The present study investigates the effect of partial hepatectomy (PH), given during a short-term exposure (4 weeks) to OA, on the development of hepatocyte nodules (HN) and hepatocellular carcinoma (HCC) initiated by diethylnitrosamine (DEN). Male Fischer 344 rats (130-150 g) were given a single dose of DEN (200 mg/kg body wt i.p.). Starting a week later they were fed either a semisynthetic basal diet (BD) or the same diet containing 1% OA for 2 weeks; two-thirds PH was then performed followed by another 2 weeks of BD or OA diet respectively. At the end of this treatment some animals from both groups were killed while the rest were continued on BD and killed at 20 or 56 weeks thereafter. The results showed no difference between the two groups in the incidence of gamma-glutamyltransferase-positive foci when rats were killed at 2 weeks after PH. However, 4 week exposure to OA coupled with PH significantly enhanced the incidence of HN and HCC when this protocol was followed by 20 or 56 weeks of BD feeding respectively, leading to 63% incidence of HCC in the OA-fed group, while no HCC was observed in control animals. It is concluded that a type of stable or permanent change(s) ('imprinting' or 'memory effect') is induced in the initiated rat liver by this treatment, which imposes a promoting environment in the liver even after withdrawal of the promoter.

Animals↗
PubMed1993

The effect of orotic acid treatment on the energy and carbohydrate metabolism of the hypertrophying rat heart.

1. Adenine nucleotide concentrations in normal and one day hypertrophied hearts of untreated, orotic acid (OA), uridine, uracil, dihydroorotate and reserpine pretreated rats were measured. OA treatment increased the ADP concentration 5-fold in one day hypertrophied hearts. Neither uracil, uridine, dihydroorotate nor reserpine treatments changed ADP or total adenylate concentrations at one day of hypertrophy. 2. The adenine nucleotide ratio (ANR) at 0.263 x 10(3) M-1 and the energy charge (0.66) were at their lowest values in OA and in reserpine treated one day hypertrophying hearts. The temporal decline in the indices of energy metabolism corresponded with the OA induced maximum stimulation of contractility and maximum rates of protein, RNA and glycogen synthesis. 3. The phosphorylation state of the adenine nucleotides (PSAN) was both the most sensitive and the best predictive index of the cellular energy status in normal and hypertrophying hearts. The pronounced ability of OA treatment to energize myocyte cytoplasm was shown by the 9- and 6-fold greater values of PSAN over ANR in one and three day hypertrophied hearts. The enhanced PSAN may be the key factor in the mechanism of OA induced enhancement of contractile and synthetic functions of the heart in compensatory hypertrophy. 4. The development of myocardial hypertrophy in untreated rats resulted in a 36% reduction in the cytoplasmic NAD/NADH ratio. In rats treated with OA this redox couple of the hypertrophying heart was more oxidized and was increased by 30% to restore it to the value range of normal heart. 5. The regulatory status of the glycolytic pathway in untreated and OA treated hypertrophying hearts was assessed by comparisons of the mass action ratio (MAR) and equilibrium constants for each of the individual glycolytic reactions. There was an OA induced 2.7-fold increase in glycogen, UDP-glucose and total uridine nucleotides in hypertrophied hearts. The concentrations of seven out of ten glycolytic intermediates, including pyruvate and lactate were increased as a consequence of OA treated hypertrophy. Glycolytic flux was not stalled, rather the pathway was "more open" permitting greater throughput of intermediates with individually increased levels of selected metabolites. OA stimulated hypertrophy did not change the canonical control of glycolysis by the activities and individual MAR values of phosphofructokinase and pyruvic kinase. 6. Elevated levels of Glu 6-P, Fru 6-P and DHAP can force glycolytic intermediate entry into the non-oxidative reaction segment of the pentose pathway (PP), thereby elevating Rib 5-P concentration by reversal of the conventional flux direction of PP.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Diphosphate↗
PubMed1997

Palladium(II) compounds with potential antitumour properties and their platinum analogues: a comparative study of the reaction of some orotic acid derivatives with DNA in vitro.

Ethidium bromide was used to study perturbations induced in salmon sperm DNA complexed with a series of platinum and palladium compounds obtained from chloro and orotic acid derivatives as leaving ligands. The antitumoral activity of these compounds against Sarcoma 180 cells grafted intraperitoneally into mice is correlated with their capacity to interact with DNA in vitro and to perturb its secondary structure. Nevertheless, among these compounds, [Pt(Dach)(3-methyl-orot)] and [Pt(Dach)(5-fluoro-orot)] do not interact with DNA in vitro and are inactive against Sarcoma 180 cells. This lack of activity originates from the fact that strong chelating properties of the ligand prevent hydrolysis of the compounds which are unable to give rise to aquo species which are the reactive ones. On the other hand, the interaction with DNA is not the only prerequisite in order that a compound be active towards tumour cells. In fact, cis-[Pd(NH3)2Cl2] and cis[Pd(Dach)Cl2] are not antitumoral. It is well known that the former undergoes an inactive trans-conformation and that the two compounds hydrolyse very fast assuming that they interact in vivo with a lot of molecules particularly proteins preventing them to reach the DNA, their pharmacological target. By contrast, [Pd(Dach)(3-methyl-orot)] (T/C = 267%) and [Pd(Dach)(5-fluoro-orot)] (T/C = 270%) display significant antitumour activity.

Animals↗
PubMed1977

Effects of orotic acid and pirazetam on cortical bioelectrical activity in rabbits.

In order to obtain further evidence of the pharmacological effects of retention-facilitating substances, the influence of sodium-orotate, methylglucamine orotate, and pirazetam on the bioelectrical activity of central nervous system structures were studied. Sodium orotate showed no influence on the cortical and hippocampal spontaneous EEGs of conscious nonimmobilized rabbits. The amplitude of the first surface-positive wave of the cortical evoked potential that was elicited by stimulation of tooth pulp was, however, significantly increased in long-lasting terms by both pirazetam and the two salts of orotic acid. Similarly, the three substances also influenced the changes in excitability induced by PTP of tooth pulp. The findings suggest that these chemicals facilitate in nonspecific manner responses to externally applied stimuli through central structures. The relationships between the altered stimulus response and the retention-facilitating action of these substances are discussed.

Animals↗
PubMed1994

Orotic acid enhancement of preneoplastic and neoplastic lesions induced in the pancreas and liver of hamsters by N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine.

The effect of dietary orotic acid (OA) in liver-pancreas carcinogenesis induced in female Syrian hamsters by N-Nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) was evaluated. All animals infused with the carcinogen received the same doses. Results of the control group which received no OA or carcinogen were compared with the results of: (a) hamsters treated with HPOP and fed a regular 20% protein synthetic diet (group 1); (b) hamsters fed the OA diet for a brief time period during initiation with the carcinogen (group 2); and (c) hamsters in which OA was administered after carcinogen infusion for life (group 3). All animals of the control group were normal at autopsy, while those in group 1 (HPOP alone) revealed the spectrum of lesions accepted as classical in the multistep hyperplasia-dysplasia-carcinoma in situ (CIS) sequence of carcinogenesis. Results of group 2, in light of group 1, revealed an increased incidence of the following lesions in the common pancreatic duct: dilatation, 2.5 times; flat and papillary hyperplasia, 2 times; and dysplasia (atypical hyperplasia), 12 times. No significant increase of CIS and invasive cancer in the body and tail of the pancreas was observed; in addition, the incidence, nature, and location of pancreatic adenocarcinomas were not affected. Yet, the effect of OA administered after carcinogen infusion (group 3) when compared to group 1 seemed to enhance a further increase in the incidence of practically all lesions throughout the pancreas. An obvious overall step-up incidence along the multistep hyperplasia-dysplasia-CIS-invasive cancer process in the pancreas was observed. The increase in incidence of flat, papillary, and atypia of the epithelium of the common pancreatic duct in group 3 was mild compared to that found in the same duct of group 2, but the increase in incidence of these same three lesions when found in the main ducts was marked: flat hyperplasia, 3-fold; papillary hyperplasia, 2.5-fold; atypical hyperplasia, 3-fold. The increase in incidence of CIS in this group was 5-fold and papillary adenocarcinomas, 3-fold, when compared to 5% found in groups 1 and 2. Hepatic malignancies (cholangiocarcinomas) occurred in 6% of the cases in group 3 compared to none in group 2; the incidence of malignancy in the gallbladder was the same in groups 2 and 3 but three times greater than that in group 1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Prevention of orotic-acid-induced fatty liver in male rats by dehydroepiandrosterone and/or phenobarbital.

Dehydroepiandrosterone (DHEA) is a steroid hormone which induces the peroxisome proliferation in rodents. The fatty liver induced by orotic acid and a high sucrose diet in male rats was prevented by the administration of DHEA and/or phenobarbital (PB). A significant increase in the liver weight was induced in the DHEA group (relative weight) and the DHEA + PB group (absolute and relative weight). The liver weight increased more conspicuously in the DHEA + PB group than in the DHEA group. The increase in the liver weight was caused by an increase in the cell size and peroxisome number. In addition, the administration of DHEA alone and the combination of DHEA and PB prevented the lipid droplet accumulation in hepatocytes. The administration of PB alone also prevented the accumulation of lipid droplets without any increase in the liver weight.

Analysis of Variance↗
PubMedDate not supplied

5-fluoro-orotic acid induces chromosome alterations in genetically manipulated strains of Candida albicans.

We previously reported the occurrence of chromosome alterations in a Candida albicans prototrophic strain 3153A treated with 5-fluoro-orotic acid (5-FOA). In this study we investigated the mutagenic properties of 5-FOA with two derivatives of C. albicans strain CAF4-2 (ura3/ura3), each containing an ectopic copy of URA3 gene (ura3/ ura3 URA3) on a different chromosome. As expected, after the ura3/ura3 URA3 constructs were applied to 5-FOA containing solid medium, the "pop-outs" that lost URA3 appeared. However most of the "pop-outs" acquired various chromosome alterations. Thus constructs exposed to 5-FOA should be examined for chromosome alterations or the use of 5-FOA should be avoided.

Candida albicans↗
PubMed1979

Evidence for the operation of the extrahepatic lipoprotein receptor system in vivo in rats. Effect of dietary cholesterol and orotic acid, alone or in combination, on the rate of synthesis of cholesterol and fatty acid in various tissues, measured by using 3H2O.

1. The biosynthesis of cholesterol in vivo was studied at a number of tissue sites in rats by using 3H2O as precursor. Overall, the mass of cholesterol synthesized was in good agreement with the rate of cholesterogenesis, as determined by kinetic analysis of cholesterol specific-radioactivity-time curves after administration of radiolabelled cholesterol. 2. Dietary cholesterol increased the circulating concentration of cholesterol and inhibited endogenous cholesterogenesis, with concomitant increases in the concentration of esterified cholesterol, in all tissues studied. Addition of ororic acid to the cholesterol-supplemented diet tended to reverse each of these changes in extrahepatic tissues. 3. The co-ordinated change in cholesterol biosynthesis and esterification, with no change in total cholesterol content, in extrahepatic tissues, is attributed to control by receptor-mediated lipoprotein uptake. 4. Further reduction of the concentration of the apoprotein B-containing lipoproteins by addition of orotic acid to a diet without supplementary cholesterol did not further enhance cholesterogenesis. We consider that the relatively high rates of extrahepatic cholesterogenesis in normolipidaemic rats are attributable to the low concentration of low-density lipoprotein.

Animals↗
PubMed1993

The effect of long-term feeding of orotic acid on the incidence of foci of enzyme-altered hepatocytes and hepatic nodules in Fischer 344 rats.

The present study was designed to determine the long-term effects of orotic acid (OA), a multi-organ tumor promoter, in rats not exposed to any carcinogen. Male Fischer 344 rats (130-150 g) were divided into two groups and given either a semisynthetic basal diet (BD) or the same diet containing 1% OA. Animals from both groups were killed after 1 or 2 years of treatment. Foci of placental glutathione-S-transferase (GST 7-7) positive hepatocytes were observed in the livers of both BD and OA fed rats killed after 1 year. However, they were more in number in animals receiving OA (156 +/- 21 versus 51 +/- 11/cm3). After 2 years, hepatic nodules were seen in almost all the animals given OA and in approximately 30% of the rats given BD. The nodules were of two main types: (i) a reddish-brown type, present in 85% of rats exposed to OA and in 27% of rats given BD, and (ii) a greyish-white type, found in 50% of animals fed OA and in none of the animals fed BD. These two types of lesions were also histologically different. Reddish-brown nodules were composed of slightly enlarged hepatocytes resembling normal surrounding tissue, while greyish-white nodules were similar in structure and are indistinguishable from hepatic nodules induced by genotoxic chemical carcinogens. The results are interpreted to suggest that the foci/nodules seen in OA-fed rats are due to a promoting effect of OA on spontaneously arising and/or diet-induced altered cells.

Animals↗
PubMed1976

The metabolism of steroids in the fatty liver induced by orotic acid feeding.

1. The metabolism of 4-[4-14C]androstene-3,17-dione, 4-[4-14C]pregnene-3,20-dione, 5alpha-[4-14C]androstane-3alpha,17beta-diol, [4-14C]cholesterol, 7alpha-hydroxy-4-[6beta-3H]cholesten-3-one, 5beta-[7beta-3H]cholestane-3alpha,7alpha-diol and [3H]lithocholic acid was studied in the microsomal fraction of livers from control and orotic acid-treated male rats. 2. As a result of the treatment the orotic acid-fed rats had fatty livers and subnormal concentrations of cholesterol and triglycerides in serum. 3. The 6beta- and 7alpha-hydroxylation of 4-androstene3,17-dione, and the 2alpha-, 2beta- and 18-hydroxylation of 5alpha-androstane-3alpha,17beta-diol, and the 5alpha-reduction of 4-androstene-3,17-dione and 4-pregnene-3,20-dione were decreased by 40--50% in orotic acid-fed rats. Other oxidative and reductive reactions of the steroid hormones were not significantly affected. 4. The 12alpha-hydroxylation of 7alpha-hydroxy-4-cholesten-3-one was decreased by about 50%, whereas the 7alpha-hydroxylation of cholesterol and the 26-hydroxylation of 5beta-cholestane-3alpha,7alpha-diol were not significantly decreased. The 6beta-hydroxylation of lithocholic acid was stimulated by 40%. 5. The results are discussed in relation to present knowledge of the heapatic drug-metabolizing enzymes and to the recent findings of an abnormal bile acid metabolism in liver disease.

Androstane-3,17-diol↗
PubMed1976

[Effect of orotic acid on the in vitro cultured nerve tissue].

Cell- and explantcultures of the hippocampus of 18 days old fetal rats and explantcultures of the ganglion trigeminal of 9 days old chick embryos were cultivated in Maximow-chambers. Orotic acid, Sodiumorotate and methylglucaminorotate by concentrations of 10(-3)...10(-7) g/ml medium were added to the cultures. By concentrations of 10(-7) g/ml medium in the CNS-cultures and 10(-6) g/ml medium in the PNS-cultures is stimulated the nerve fiber growth and is increased the nerve fiber index. After three weeks in vitro is a higher number of neurons in the cultures compared to the controls.

Animals↗
PubMed1990

Platinum and palladium complexes of 3-methyl orotic acid: a route toward palladium complexes with good antitumor activity.

In order to design and develop potential anticancer drugs involving the same structural pattern as platinum(II) antitumor complexes, complexes of palladium and platinum with 3-methyl-orotic acid as the leaving ligand have been synthesized. The study of the anticancer activity of these compounds toward L1210 leukemia and sarcoma 180 in mice is presented and discussed in terms of the nature of the ligand and the metal involved. The (3-methylorotato)(1,2-diamino-cyclohexane) palladium(II) has an activity (sarcoma 180) similar to that for cis-DDP itself. The crystal structure of (3-methylorotato)(dl-trans-1,2-diaminocyclohexane) platinum(II) is described.

Animals↗
PubMed2004

Pretranslational upregulation of microsomal CYP4A in rat liver by intake of a high-sucrose, lipid-devoid diet containing orotic acid.

In rodents, high-fat diets promote hepatic lipid accumulation in rodents, activation of peroxisome proliferator activated receptor-alpha (PPARalpha) and upregulation of cytochrome P450 (CYP) 4A gene expression. Lipid-devoid diets containing sucrose and orotic acid (S/OA-diet) also cause lipid infiltration by stimulating intrahepatic lipid synthesis and preventing lipoprotein transport through the Golgi apparatus. This study evaluated the impact of the lipid-deficient S/OA-diet on CYP4A expression and PPARalpha activation in rodent liver. CYP4A protein and laurate omega-hydroxylation activity were increased in rat liver after S/OA-feeding for 21 days. CYP4A1 and CYP4A2 mRNAs were induced to 2.1- and 2.6-fold of control, but mRNAs corresponding to CYP4A3 and the peroxisomal acyl-CoA oxidase (AOX) were unchanged. Coadministration of clofibric acid and the S/OA-diet prevented hepatic lipid accumulation and upregulated CYP4A protein to levels comparable with clofibric acid alone (five-fold of control). Clofibric acid, alone and in combination with the S/OA-diet, upregulated CYP4A1-3 and AOX mRNAs. Hepatic PPARalpha protein was decreased by the S/OA-diet but was increased to 5.7-fold of control by clofibric acid; retinoid X-receptor-alpha (RXRalpha) protein was decreased to 26-41% of control by all treatments. In further studies, administration of the S/OA-diet to control and PPARalpha-null mice promoted hepatic lipid deposition; microsomal CYP4A protein was induced in wild-type but not PPARalpha-null mice. These findings implicate PPARalpha in the induction of CYP4A in rodent liver by the lipid-devoid S/OA-diet. Decreased availability of hepatic PPARalpha and RXRalpha after intake of the diet may contribute to the selective upregulation of hepatic CYP4A1 and CYP4A2 in this model.

Animals↗
PubMed2003

Determination of orotic acid in urine by capillary zone electrophoresis in tandem-coupled columns with diode array detection.

Analytical potentialities of capillary zone electrophoresis in the separation system with tandem-coupled columns to the spectral identification and determination of orotic acid (OA) in urine by diode array detection (DAD), coupled to the separation system via optical fibers, were investigated. A very significant "in-column" clean-up of OA from urine matrix was reached in the separation stage of the tandem by combining a low pH (2.8) with complexing effects of electroneutral agents [alpha- and beta-cyclodextrins, poly(vinylpyrrolidone) and 3-(N,N-dimethyldodecylammonio)propanesulfonate]. Due to this, its DAD spectral data could be acquired in the detection stage of the tandem with almost no disturbances by matrix co-migrants. The concentration limits of detection obtained under such working conditions for a 200-nl sample load of OA and 320 microm I.D. capillary tubes were 3.5 micromol/l (218 nm) and 0.4 micromol/l (280 nm). Using chemometry procedures (target transformation factor analysis, fixed size moving window-evolving factor analysis, orthogonal projection approach and fixed size moving window-target transformation factor analysis) in processing of the acquired spectral data, the presence of OA in the loaded urine matrix could be confirmed with confidence when its concentration was 10 micromol/l or slightly less.

Electrophoresis, Capillary↗